Anti-interleukin-33 antibodies and uses thereof

Abstract

Provided are isolated antibodies or antigen-binding fragments thereof that specifically bind to IL-33, and methods of making and using the same, e.g., for the treatment of IL-33-mediated diseases.SOLUTION: An isolated antibody, or antigen-binding fragment thereof, that specifically binds to IL-33, wherein the antibody comprises in a binding domain comprising a heavy chain variable (VH) domain and a light chain variable (VL) domain: A binding domain comprising the following six complementary determining regions (CDRs): (a) CDR - H1 comprising the amino acid sequence of NYWMT; (b) CDR - H2 comprising the amino acid sequence of SITTTGGGTYYPDSVKG; (c) CDR - H3 comprising the amino acid sequence of ANYYYNTYGGFPY; (d) CDR - L1 comprising the amino acid sequence of LASEGFSNDLA; (e) CDR - L2 comprising the amino acid sequence of AASRLQD; and (f) CDR - L3 comprising the amino acid sequence of QQGSKYPLT.SELECTED DRAWING: None

Description

[Technical Field]

[0001] Sequence Listing This application contains a Sequence Listing that has been submitted electronically in ASCII format and is incorporated herein by reference in its entirety. The ASCII copy was created on February 26, 2021, is named 50474-219WO3_Sequence_Listing_2_26_21_ST25, and is 68,754 bytes in size.

[0002] The present invention relates to anti-interleukin-33 (IL-33) antibodies and methods for making and using them, including for the treatment of IL-33-mediated disorders. [Background technology]

[0003] Age-related macular degeneration (AMD) is the leading cause of irreversible blindness in people over 50 years of age in developed countries. The majority of visual impairment occurs in advanced AMD, which has two clinical forms: nonexudative geographic atrophy (GA), characterized by loss of photoreceptors, retinal pigment epithelium (RPE), and choriocapillaris, and exudative or wet form, characterized by choroidal neovascularization (CNV). In the early stages of GA, patients typically exhibit minimal changes in central visual acuity (VA). However, even though central VA may not yet be affected, patients often experience significant symptoms of visual dysfunction, including dense parafoveal scotoma (leading to impaired face recognition, for example), delayed dark adaptation, reduced contrast sensitivity, and decreased reading speed. In later stages, as GA lesions extend to the fovea, significant decline in central VA occurs, along with a decline in activities of daily living. Furthermore, GA is bilateral in most patients with advanced AMD. GA is a significant cause of both moderate and severe central vision loss. Currently, there are no approved treatments for GA, and with more than 5 million patients worldwide, there is a high unmet medical need.

[0004] Interleukin-33 (IL-33), encoded by the IL33 gene, is a member of the interleukin-1 (IL-1) cytokine family and is expressed in structural cells, such as smooth muscle, epithelium (e.g., retinal pigment epithelial (RPE) cells), endothelial cells (e.g., choroidal endothelial cells), Müller cells, and astrocytes. IL-33 can be induced by inflammatory factors in macrophages and dendritic cells. Cellular stress caused by environmental factors, such as allergens, toxins, and pathogens, can lead to IL-33 release. For example, IL-33 is released from Müller cells during phototoxic stress and induces CCL2- and monocyte-dependent retinal degeneration in preclinical models. Bioavailable IL-33 binds to the heterodimeric IL-33 receptor complex, consisting of the suppressor of tumorigenicity 2 (ST2) protein and interleukin-1 receptor accessory protein (IL-1RAcP), to activate the AP-1 and NF-κB pathways through the adaptor proteins myeloid differentiation primary response 88 (MyD88) and, optionally, MyD88 adaptor-like (Mal) protein. IL-33 stimulates multiple cell types, including innate type II (ILC2) cells, mast cells, basophils, eosinophils, and dendritic cells, promoting type 2 immunity.

[0005] The IL-33 pathway has been implicated in a variety of diseases, including ocular diseases (e.g., GA), for which there remains a need to develop improved compositions and treatment methods. Summary of the Invention

[0006] The present invention relates, inter alia, to anti-IL-33 antibodies and methods for making and using same.

[0007] In one aspect, provided herein is an isolated antibody, or antigen-binding fragment thereof, that specifically binds to IL-33, wherein the antibody comprises a binding domain comprising a heavy chain variable (VH) domain and a light chain variable (VL) domain, the binding domain comprising the following six complementarity determining regions (CDRs): (a) CDR-H1 comprising the amino acid sequence of NYWMT (SEQ ID NO: 1); (b) CDR-H2 comprising the amino acid sequence of SITYTGGGTYYPDSVKG (SEQ ID NO: 2); (c) CDR-H3 comprising the amino acid sequence of ANYYYNTYGGFPY (SEQ ID NO: 3); (d) CDR-L1 comprising the amino acid sequence of LASEGFSNDLA (SEQ ID NO: 4); (e) CDR-L2 comprising the amino acid sequence of AASRLQD (SEQ ID NO: 5); and (f) CDR-L3 comprising the amino acid sequence of QQGSKYPLT (SEQ ID NO: 6).

[0008] In another aspect, provided herein is an isolated antibody, or antigen-binding fragment thereof, that specifically binds to IL-33, wherein the antibody comprises: (a) a VH domain comprising an amino acid sequence having at least 95% sequence identity to the amino acid sequence of SEQ ID NO: 7; (b) a VL domain comprising an amino acid sequence having at least 95% sequence identity to the amino acid sequence of SEQ ID NO: 8; or (c) a binding domain comprising the VH domain of (a) and the VL domain of (b).

[0009] In some embodiments, the VH domain is (a) EVQLVX1SGX2X3X4X5X6PGX7SX8X9X 10 SCX 11 FR-H1 comprising the amino acid sequence of ASGFTFN (SEQ ID NO: 9), where X1 is E or Q; X2 is G or A; X3 is G or E; X4 is L or V; X5 is V or K; X6 is Q or K; X7 is G, A, or T; X8 is L or V; X9 is R or K; and X 10 is L or V; X 11is A, K, or L; (b) FR-H2 comprising the amino acid sequence of WX1RQAPGX2GLEWX3X4 (SEQ ID NO: 10) (wherein X1 is I or V; X2 is K or Q; X3 is V, M, or I; and X4 is A or G); (c) RX1TX2X3RDX4X5X6X7X8X9YX 10 X 11 X 12 X 13 SLRX 14 EDTAX 15 FR-H3 comprising the amino acid sequence of YYCTR (SEQ ID NO: 11) (wherein X1 is F or V; X2 is I or M; X3 is S or T; X4 is D, N, or T; X5 is A or S; X6 is K or T; X7 is S or N; X8 is S or T; X9 is L or V; and X 10 is L or M; X 11 is Q or E; X 12 is M or L; X 13 is N or S; X 14 is A or S; X 15 is V or T); and (d) FR-H4 comprising the amino acid sequence WGQGTLVTVSS (SEQ ID NO: 12).

[0010] In some aspects, the VH domain comprises: (a) FR-H1 comprising the amino acid sequence of EVQLVESGGGLVQPGGSLRLSCAASGFTFN (SEQ ID NO: 17); (b) FR-H2 comprising the amino acid sequence of WIRQAPGKGLEWVA (SEQ ID NO: 18); (c) FR-H3 comprising the amino acid sequence of RFTISRDDAKSSLYLQMNSLRAEDTAVYYCTR (SEQ ID NO: 19); and (d) FR-H4 comprising the amino acid sequence of WGQGTLVTVSS (SEQ ID NO: 12).

[0011] In some embodiments, the VH domain comprises the amino acid sequence of SEQ ID NO:7.

[0012] In some aspects, the VH domain comprises: (a) FR-H1 comprising the amino acid sequence of EVQLVESGGGLVQPGGSLRLSCAASGFTFN (SEQ ID NO: 17); (b) FR-H2 comprising the amino acid sequence of WVRQAPGKGLEWVA (SEQ ID NO: 39); (c) FR-H3 comprising the amino acid sequence of RFTISRDNAKNSLYLQMNSLRAEDTAVYYCTR (SEQ ID NO: 40); and (d) FR-H4 comprising the amino acid sequence of WGQGTLVTVSS (SEQ ID NO: 12).

[0013] In some embodiments, the VH domain comprises the amino acid sequence of SEQ ID NO:41.

[0014] In some aspects, the VH domain comprises: (a) FR-H1 comprising the amino acid sequence of EVQLVESGGGLVQPGGSLRLSCAASGFTFN (SEQ ID NO: 17); (b) FR-H2 comprising the amino acid sequence of WIRQAPGKGLEWIA (SEQ ID NO: 42); (c) FR-H3 comprising the amino acid sequence of RFTISRDDAKSSLYLQMNSLRAEDTAVYYCTR (SEQ ID NO: 19); and (d) FR-H4 comprising the amino acid sequence of WGQGTLVTVSS (SEQ ID NO: 12).

[0015] In some embodiments, the VH domain comprises the amino acid sequence of SEQ ID NO:43.

[0016] In some aspects, the VH domain comprises: (a) FR-H1 comprising the amino acid sequence of EVQLVESGGGLVQPGGSLRLSCAASGFTFN (SEQ ID NO: 17); (b) FR-H2 comprising the amino acid sequence of WVRQAPGKGLEWVA (SEQ ID NO: 39); (c) FR-H3 comprising the amino acid sequence of RFTISRDDAKSSLYLQMNSLRAEDTAVYYCTR (SEQ ID NO: 19); and (d) FR-H4 comprising the amino acid sequence of WGQGTLVTVSS (SEQ ID NO: 12).

[0017] In some embodiments, the VH domain comprises the amino acid sequence of SEQ ID NO:44.

[0018] In some aspects, the VH domain comprises: (a) FR-H1 comprising the amino acid sequence of EVQLVESGGGLVQPGGSLRLSCAASGFTFN (SEQ ID NO: 17); (b) FR-H2 comprising the amino acid sequence of WVRQAPGKGLEWVA (SEQ ID NO: 39); (c) FR-H3 comprising the amino acid sequence of RFTISRDDAKNSLYLQMNSLRAEDTAVYYCTR (SEQ ID NO: 45); and (d) FR-H4 comprising the amino acid sequence of WGQGTLVTVSS (SEQ ID NO: 12).

[0019] In some embodiments, the VH domain comprises the amino acid sequence of SEQ ID NO:46.

[0020] In some aspects, the VH domain comprises: (a) FR-H1 comprising the amino acid sequence of EVQLVESGGGLVQPGGSLRLSCAASGFTFN (SEQ ID NO: 17); (b) FR-H2 comprising the amino acid sequence of WVRQAPGKGLEWVA (SEQ ID NO: 39); (c) FR-H3 comprising the amino acid sequence of RFTISRDNAKSSLYLQMNSLRAEDTAVYYCTR (SEQ ID NO: 47); and (d) FR-H4 comprising the amino acid sequence of WGQGTLVTVSS (SEQ ID NO: 12).

[0021] In some embodiments, the VH domain comprises the amino acid sequence of SEQ ID NO:48.

[0022] In some aspects, the VH domain comprises: (a) FR-H1 comprising the amino acid sequence of EVQLVESGGGLVQPGGSLRLSCAASGFTFN (SEQ ID NO: 17); (b) FR-H2 comprising the amino acid sequence of WVRQAPGKGLEWIA (SEQ ID NO: 49); (c) FR-H3 comprising the amino acid sequence of RFTISRDDAKSSLYLQMNSLRAEDTAVYYCTR (SEQ ID NO: 19); and (d) FR-H4 comprising the amino acid sequence of WGQGTLVTVSS (SEQ ID NO: 12).

[0023] In some embodiments, the VH domain comprises the amino acid sequence of SEQ ID NO:50.

[0024] In some aspects, the VH domain comprises: (a) FR-H1 comprising the amino acid sequence of EVQLVESGGGLVQPGGSLRLSCAASGFTFN (SEQ ID NO: 17); (b) FR-H2 comprising the amino acid sequence of WVRQAPGKGLEWIA (SEQ ID NO: 49); (c) FR-H3 comprising the amino acid sequence of RFTISRDDSKSTLYLQMNSLRAEDTAVYYCTR (SEQ ID NO: 51); and (d) FR-H4 comprising the amino acid sequence of WGQGTLVTVSS (SEQ ID NO: 12).

[0025] In some embodiments, the VH domain comprises the amino acid sequence of SEQ ID NO:52.

[0026] In some embodiments, the VL domain is (a) X1IX2X3TQSPX4X5LSX6SX7GX8X9X 10 X 11 X 12 X 13 FR-L1 comprising the amino acid sequence of X1, X2, X3, X4, X5, X6, X7, X8, X9, X10, X11, X12, X13, X14, X15, X16, X17, X18, X19, X20, X21, X22, X23, X24, X25, X26, X27, X28, X29, X30, X31, X32, X33, X34, X35, X36, X37, X38, X39, X40, X41, X42, X43, X44, X45, X46, X47, X48, X49, X50, X51, X52, X53, X54, X55, X56, X57, X58, X59, X60, X61, X62, X63, X64, X65, X66, X67, X68, X69, X70, X71, X72, X73, X74, X75, X76, X77, X78, X79, X80, X81, X82, X83, X84, X85, X86, X87, X88, X89, X90, X91, X92, X93, X94, X95, X96, X97, X98, X99, X99, X91, X95, X96, X97, X98, X99, X99, X99, X100, X101, X110, X111, X121, X122, X123, X124, X125, X130, X131, X132, X141, X142, X143, X1 10 is V or A; X 11 is T or S; X 12 is I or L; X 13 is T, S, or E; (b) FR-L2 comprising the amino acid sequence of WX1QQKX2GX3X4PX5X6LIY (SEQ ID NO: 14) (wherein X1 is Y or F; X2 is P or S; X3 is K or Q; X4 is S or A; X5 is K, R, or Q; and X6 is L or S); (c) GX1PX2RFSGSGSGTX3FX4LX5ISX6X7X8PEDX9AX 10 YX 11 FR-L3 comprising the amino acid sequence of X1, X2, X3, X4, X5, X6, X7, X8, X9, X10, X11, X12, X13, X14, X15, X16, X17, X18, X19, X20, X21, X22, X23, X24, X25, X26, X27, X28, X29, X30, X31, X32, X33, X34, X35, X36, X37, X38, X39, X40, X41, X42, X43, X44, X45, X46, X47, X48, X49, X50, X51, X52, X53, X54, X55, X56, X57, X58, X59, X60, X61, X62, X63, X64, X65, X66, X77, X78, X79, X81, X82, X83, X84, X85, X86, X87, X88, X89, X90, X91, X92, X93, X94, X95, X96, X97, X98, X99, X99, X91, X92, X94, X95, X95, X96, X97, X98, X99, X99, X99, X99, X100, X101, X110, X111, X121, X122, X123, X124, X125, X126, X127, X128, X129, X130, X131, X132, X141, X142, X143, X144, X145, 10is T, V, or D; X 11 is F or Y); and (d) FR-L4 comprising the amino acid sequence of FGX1GTKX2EIK (SEQ ID NO: 16), where X1 is G or S and X2 is V or L.

[0027] In some aspects, the VL domain comprises: (a) FR-L1 comprising the amino acid sequence of DIQMTQSPSSLSASVGDRVTITC (SEQ ID NO: 21); (b) FR-L2 comprising the amino acid sequence of WYQQKPGKSPKLLIY (SEQ ID NO: 22); (c) FR-L3 comprising the amino acid sequence of GVPSRFSGSGSGTDFTLTISSLQPEDFATYFC (SEQ ID NO: 23); and (d) FR-L4 comprising the amino acid sequence of FGGGTKVEIK (SEQ ID NO: 24).

[0028] In some embodiments, the VL domain comprises the amino acid sequence of SEQ ID NO:8.

[0029] In another aspect, provided herein is an isolated antibody, or antigen-binding fragment thereof, that specifically binds to IL-33, wherein the antibody comprises a binding domain comprising (a) a VH domain comprising the amino acid sequence of SEQ ID NO:7 and (b) a VL domain comprising the amino acid sequence of SEQ ID NO:8.

[0030] In another aspect, provided herein is an isolated antibody, or antigen-binding fragment thereof, that specifically binds to IL-33, wherein the antibody comprises a binding domain comprising (a) a heavy chain (HC) comprising the amino acid sequence of SEQ ID NO:25 and (b) a light chain (LC) comprising the amino acid sequence of SEQ ID NO:26.

[0031] In some aspects, the VL domain comprises: (a) FR-L1 comprising the amino acid sequence of DIQMTQSPSSLSASVGDRVTITC (SEQ ID NO: 21); (b) FR-L2 comprising the amino acid sequence of WFQQKPGKAPKSLIY (SEQ ID NO: 53); (c) FR-L3 comprising the amino acid sequence of GVPSRFSGSGSGTDFTLTISSLQPEDFATYYC (SEQ ID NO: 54); and (d) FR-L4 comprising the amino acid sequence of FGGGTKVEIK (SEQ ID NO: 24).

[0032] In some embodiments, the VL domain comprises the amino acid sequence of SEQ ID NO:55.

[0033] In some aspects, the VL domain comprises: (a) FR-L1 comprising the amino acid sequence of DIQMTQSPSSLSASVGDRVTITC (SEQ ID NO: 21); (b) FR-L2 comprising the amino acid sequence of WYQQKPGKAPKSLIY (SEQ ID NO: 56); (c) FR-L3 comprising the amino acid sequence of GVPSRFSGSGSGTDFTLTISSLQPEDFATYFC (SEQ ID NO: 23); and (d) FR-L4 comprising the amino acid sequence of FGGGTKVEIK (SEQ ID NO: 24).

[0034] In some embodiments, the VL domain comprises the amino acid sequence of SEQ ID NO:57.

[0035] In some aspects, the VL domain comprises: (a) FR-L1 comprising the amino acid sequence of DIQMTQSPSSLSASVGDRVTITC (SEQ ID NO: 21); (b) FR-L2 comprising the amino acid sequence of WFQQKPGKAPKSLIY (SEQ ID NO: 53); (c) FR-L3 comprising the amino acid sequence of GVPSRFSGSGSGTDFTLTISSLQPEDFATYFC (SEQ ID NO: 23); and (d) FR-L4 comprising the amino acid sequence of FGGGTKVEIK (SEQ ID NO: 24).

[0036] In some embodiments, the VL domain comprises the amino acid sequence of SEQ ID NO:58.

[0037] In some aspects, the VL domain comprises: (a) FR-L1 comprising the amino acid sequence of DIQMTQSPSSLSASVGDRVTITC (SEQ ID NO: 21); (b) FR-L2 comprising the amino acid sequence of WYQQKPGKAPKSLIY (SEQ ID NO: 56); (c) FR-L3 comprising the amino acid sequence of GVPSRFSGSGSGTDFTLTISSLQPEDFATYYC (SEQ ID NO: 54); and (d) FR-L4 comprising the amino acid sequence of FGGGTKVEIK (SEQ ID NO: 24).

[0038] In some embodiments, the VL domain comprises the amino acid sequence of SEQ ID NO:59.

[0039] In some aspects, the VL domain comprises: (a) FR-L1 comprising the amino acid sequence of DIQMTQSPSSLSASVGDRVTITC (SEQ ID NO: 21); (b) FR-L2 comprising the amino acid sequence of WYQQKPGKSPKLLIY (SEQ ID NO: 22); (c) FR-L3 comprising the amino acid sequence of GVPSRFSGSGSGTDFTLTISSLQPEDVATYYC (SEQ ID NO: 60); and (d) FR-L4 comprising the amino acid sequence of FGGGTKVEIK (SEQ ID NO: 24).

[0040] In some embodiments, the VL domain comprises the amino acid sequence of SEQ ID NO:61.

[0041] In another aspect, provided herein is an isolated antibody, or antigen-binding fragment thereof, that specifically binds to IL-33, wherein the antibody comprises a binding domain comprising (a) a VH domain comprising the amino acid sequence of SEQ ID NO: 41 and (b) a VL domain comprising the amino acid sequence of SEQ ID NO: 55.

[0042] In another aspect, provided herein is an isolated antibody, or antigen-binding fragment thereof, that specifically binds to IL-33, wherein the antibody comprises a binding domain comprising (a) a VH domain comprising the amino acid sequence of SEQ ID NO: 43 and (b) a VL domain comprising the amino acid sequence of SEQ ID NO: 55.

[0043] In another aspect, provided herein is an isolated antibody, or antigen-binding fragment thereof, that specifically binds to IL-33, wherein the antibody comprises a binding domain comprising (a) a VH domain comprising the amino acid sequence of SEQ ID NO: 41 and (b) a VL domain comprising the amino acid sequence of SEQ ID NO: 8.

[0044] In another aspect, provided herein is an isolated antibody, or antigen-binding fragment thereof, that specifically binds to IL-33, wherein the antibody comprises a binding domain comprising (a) a VH domain comprising the amino acid sequence of SEQ ID NO: 43 and (b) a VL domain comprising the amino acid sequence of SEQ ID NO: 8.

[0045] In another aspect, provided herein is an isolated antibody, or antigen-binding fragment thereof, that specifically binds to IL-33, wherein the antibody comprises a binding domain comprising (a) a VH domain comprising the amino acid sequence of SEQ ID NO: 44 and (b) a VL domain comprising the amino acid sequence of SEQ ID NO: 8.

[0046] In another aspect, provided herein is an isolated antibody, or antigen-binding fragment thereof, that specifically binds to IL-33, wherein the antibody comprises a binding domain comprising (a) a VH domain comprising the amino acid sequence of SEQ ID NO: 46 and (b) a VL domain comprising the amino acid sequence of SEQ ID NO: 8.

[0047] In another aspect, provided herein is an isolated antibody, or antigen-binding fragment thereof, that specifically binds to IL-33, wherein the antibody comprises a binding domain comprising (a) a VH domain comprising the amino acid sequence of SEQ ID NO: 48 and (b) a VL domain comprising the amino acid sequence of SEQ ID NO: 8.

[0048] In another aspect, provided herein is an isolated antibody, or antigen-binding fragment thereof, that specifically binds to IL-33, wherein the antibody comprises a binding domain comprising (a) a VH domain comprising the amino acid sequence of SEQ ID NO: 43 and (b) a VL domain comprising the amino acid sequence of SEQ ID NO: 57.

[0049] In another aspect, provided herein is an isolated antibody, or antigen-binding fragment thereof, that specifically binds to IL-33, wherein the antibody comprises a binding domain comprising (a) a VH domain comprising the amino acid sequence of SEQ ID NO: 44 and (b) a VL domain comprising the amino acid sequence of SEQ ID NO: 57.

[0050] In another aspect, provided herein is an isolated antibody, or antigen-binding fragment thereof, that specifically binds to IL-33, wherein the antibody comprises a binding domain comprising (a) a VH domain comprising the amino acid sequence of SEQ ID NO: 46 and (b) a VL domain comprising the amino acid sequence of SEQ ID NO: 57.

[0051] In another aspect, provided herein is an isolated antibody, or antigen-binding fragment thereof, that specifically binds to IL-33, wherein the antibody comprises a binding domain comprising (a) a VH domain comprising the amino acid sequence of SEQ ID NO: 48 and (b) a VL domain comprising the amino acid sequence of SEQ ID NO: 57.

[0052] In another aspect, provided herein is an isolated antibody, or antigen-binding fragment thereof, that specifically binds to IL-33, wherein the antibody comprises a binding domain comprising (a) a VH domain comprising the amino acid sequence of SEQ ID NO: 50 and (b) a VL domain comprising the amino acid sequence of SEQ ID NO: 57.

[0053] In another aspect, provided herein is an isolated antibody, or antigen-binding fragment thereof, that specifically binds to IL-33, wherein the antibody comprises a binding domain comprising (a) a VH domain comprising the amino acid sequence of SEQ ID NO: 43 and (b) a VL domain comprising the amino acid sequence of SEQ ID NO: 58.

[0054] In another aspect, provided herein is an isolated antibody, or antigen-binding fragment thereof, that specifically binds to IL-33, wherein the antibody comprises a binding domain comprising (a) a VH domain comprising the amino acid sequence of SEQ ID NO: 44 and (b) a VL domain comprising the amino acid sequence of SEQ ID NO: 58.

[0055] In another aspect, provided herein is an isolated antibody, or antigen-binding fragment thereof, that specifically binds to IL-33, wherein the antibody comprises a binding domain comprising (a) a VH domain comprising the amino acid sequence of SEQ ID NO: 46 and (b) a VL domain comprising the amino acid sequence of SEQ ID NO: 58.

[0056] In another aspect, provided herein is an isolated antibody, or antigen-binding fragment thereof, that specifically binds to IL-33, wherein the antibody comprises a binding domain comprising (a) a VH domain comprising the amino acid sequence of SEQ ID NO: 48 and (b) a VL domain comprising the amino acid sequence of SEQ ID NO: 58.

[0057] In another aspect, provided herein is an isolated antibody, or antigen-binding fragment thereof, that specifically binds to IL-33, wherein the antibody comprises a binding domain comprising (a) a VH domain comprising the amino acid sequence of SEQ ID NO: 50 and (b) a VL domain comprising the amino acid sequence of SEQ ID NO: 58.

[0058] In another aspect, provided herein is an isolated antibody, or antigen-binding fragment thereof, that specifically binds to IL-33, wherein the antibody comprises a binding domain comprising (a) a VH domain comprising the amino acid sequence of SEQ ID NO: 43 and (b) a VL domain comprising the amino acid sequence of SEQ ID NO: 59.

[0059] In another aspect, provided herein is an isolated antibody, or antigen-binding fragment thereof, that specifically binds to IL-33, wherein the antibody comprises a binding domain comprising (a) a VH domain comprising the amino acid sequence of SEQ ID NO: 44 and (b) a VL domain comprising the amino acid sequence of SEQ ID NO: 59.

[0060] In another aspect, provided herein is an isolated antibody, or antigen-binding fragment thereof, that specifically binds to IL-33, wherein the antibody comprises a binding domain comprising (a) a VH domain comprising the amino acid sequence of SEQ ID NO: 46 and (b) a VL domain comprising the amino acid sequence of SEQ ID NO: 59.

[0061] In another aspect, provided herein is an isolated antibody, or antigen-binding fragment thereof, that specifically binds to IL-33, wherein the antibody comprises a binding domain comprising (a) a VH domain comprising the amino acid sequence of SEQ ID NO: 48 and (b) a VL domain comprising the amino acid sequence of SEQ ID NO: 59.

[0062] In another aspect, provided herein is an isolated antibody, or antigen-binding fragment thereof, that specifically binds to IL-33, wherein the antibody comprises a binding domain comprising (a) a VH domain comprising the amino acid sequence of SEQ ID NO:50 and (b) a VL domain comprising the amino acid sequence of SEQ ID NO:59.

[0063] In another aspect, provided herein is an isolated antibody, or antigen-binding fragment thereof, that specifically binds to IL-33, wherein the antibody comprises a binding domain comprising (a) a VH domain comprising the amino acid sequence of SEQ ID NO: 52 and (b) a VL domain comprising the amino acid sequence of SEQ ID NO: 61.

[0064] In another aspect, provided herein is an isolated antibody, or antigen-binding fragment thereof, that specifically binds to IL-33, wherein the antibody comprises: (a) a VH domain comprising an amino acid sequence having at least 95% sequence identity to the amino acid sequence of SEQ ID NO: 35; (b) a VL domain comprising an amino acid sequence having at least 95% sequence identity to the amino acid sequence of SEQ ID NO: 36; or (c) a binding domain comprising the VH domain described in (a) and the VL domain described in (b).

[0065] In some aspects, the VH domain comprises: (a) FR-H1 comprising the amino acid sequence of EVQLVESGGGLVQPGTSLKLSCLASGFTFN (SEQ ID NO: 27); (b) FR-H2 comprising the amino acid sequence of WIRQAPGKGLEWIA (SEQ ID NO: 28); (c) FR-H3 comprising the amino acid sequence of RFTISRDDAKSTLYLQMNSLRSEDTATYYCTR (SEQ ID NO: 29); and (d) FR-H4 comprising the amino acid sequence of WGQGTLVTVSS (SEQ ID NO: 12).

[0066] In some embodiments, the VH domain comprises the amino acid sequence of SEQ ID NO:35.

[0067] In some aspects, the VL domain comprises (a) FR-L1 comprising the amino acid sequence of DIQMTQSPASLSASLGETVSIEC (SEQ ID NO: 31); (b) FR-L2 comprising the amino acid sequence of WYQQKSGKSPQLLIY (SEQ ID NO: 32); (a) FR-L3 comprising the amino acid sequence of GVPSRFSGSGSGTRFSLKISGMQPEDEADYFC (SEQ ID NO: 33); and (d) FR-L4 comprising the amino acid sequence of FGSGTKLEIK (SEQ ID NO: 34).

[0068] In some embodiments, the VL domain comprises the amino acid sequence of SEQ ID NO:36.

[0069] In another aspect, provided herein is an isolated antibody, or antigen-binding fragment thereof, that specifically binds to IL-33, wherein the antibody comprises a binding domain comprising (a) a VH domain comprising the amino acid sequence of SEQ ID NO: 35 and (b) a VL domain comprising the amino acid sequence of SEQ ID NO: 36.

[0070] In another aspect, provided herein is an isolated antibody that specifically binds to IL-33, wherein the antibody comprises a binding domain comprising (a) a heavy chain (HC) comprising the amino acid sequence of SEQ ID NO: 37 and (b) a light chain (LC) comprising the amino acid sequence of SEQ ID NO: 38.

[0071] In another aspect, provided herein is an isolated antibody, or antigen-binding fragment thereof, that specifically binds to IL-33, wherein the antibody comprises: (a) a VH domain comprising an amino acid sequence having at least 95% sequence identity to the amino acid sequence of SEQ ID NO: 65; (b) a VL domain comprising an amino acid sequence having at least 95% sequence identity to the amino acid sequence of SEQ ID NO: 69; or (c) a binding domain comprising the VH domain of (a) and the VL domain of (b).

[0072] In some aspects, the VH domain comprises: (a) FR-H1 comprising the amino acid sequence of EVQLVQSGAEVKKPGASVKVSCKASGFTFN (SEQ ID NO: 62); (b) FR-H2 comprising the amino acid sequence of WVRQAPGQGLEWMG (SEQ ID NO: 63); (c) FR-H3 comprising the amino acid sequence of RVTMTRDTSTSTVYMELSSLRSEDTAVYYCTR (SEQ ID NO: 64); and (d) FR-H4 comprising the amino acid sequence of WGQGTLVTVSS (SEQ ID NO: 12).

[0073] In some embodiments, the VH domain comprises the amino acid sequence of SEQ ID NO:65.

[0074] In some aspects, the VL domain comprises: (a) FR-L1 comprising the amino acid sequence of EIVLTQSPATLSLSPGERATLSC (SEQ ID NO: 66); (b) FR-L2 comprising the amino acid sequence of WYQQKPGQAPRLLIY (SEQ ID NO: 67); (c) FR-L3 comprising the amino acid sequence of GIPARFSGSGSGTDFTLTISSLEPEDFAVYYC (SEQ ID NO: 68); and (d) FR-L4 comprising the amino acid sequence of FGGGTKVEIK (SEQ ID NO: 24).

[0075] In some embodiments, the VL domain comprises the amino acid sequence of SEQ ID NO:69.

[0076] In another aspect, provided herein is an isolated antibody, or antigen-binding fragment thereof, that specifically binds to IL-33, wherein the antibody comprises a binding domain comprising (a) a VH domain comprising the amino acid sequence of SEQ ID NO: 65 and (b) a VL domain comprising the amino acid sequence of SEQ ID NO: 69.

[0077] In some embodiments, the antibody specifically binds to human or cyno IL-33.

[0078] In some embodiments, the antibody specifically binds to both human and cyno IL-33.

[0079] In some embodiments, the antibody has a K of about 1 nM or less. D It specifically binds to both human and cyno IL-33.

[0080] In some embodiments, the antibody has a K between about 100 fM and about 1 nM. D It specifically binds to human IL-33.

[0081] In some embodiments, the antibody has a K between about 750 fM and about 300 pM. D It specifically binds to human IL-33.

[0082] In some embodiments, the antibody has a K between about 1 pM and about 200 pM. D It specifically binds to human IL-33.

[0083] In some embodiments, the antibody has a K D It specifically binds to human IL-33.

[0084] In some embodiments, the antibody has a K D It specifically binds to human IL-33.

[0085] In some embodiments, the antibody has a K between about 100 fM and about 1 nM. D It specifically binds to cyno IL-33.

[0086] In some embodiments, the antibody has a K between about 1 pM and about 500 pM. D It specifically binds to cyno IL-33.

[0087] In some embodiments, the antibody has a K between about 20 pM and about 50 pM. D It specifically binds to cyno IL-33.

[0088] In some embodiments, the antibody has a K D It specifically binds to cyno IL-33.

[0089] In some embodiments, the antibody has a K between about 1 pM and about 500 pM. D It specifically binds to both human and cyno IL-33.

[0090] In some embodiments, the antibody has a K between about 10 pM and about 40 pM. D It specifically binds to both human and cyno IL-33.

[0091] In some embodiments, the antibody is capable of inhibiting the binding of IL-33 to an IL-33 receptor.

[0092] In some embodiments, inhibition is measured using a cell-based blocking assay.

[0093] In some embodiments, the antibody inhibits the binding of human IL-33 to an IL-33 receptor with an IC50 of between about 800 fM and about 100 pM.

[0094] In some embodiments, the IC50 is between about 1 pM and about 50 pM.

[0095] In some embodiments, the IC50 is about 31 pM.

[0096] In some embodiments, the antibody has a viscosity of less than about 5 centipoise (cP) at a concentration of about 180 mg / mL.

[0097] In some embodiments, the antibody has a viscosity of between about 3 cP and about 5 cP at a concentration of about 180 mg / mL.

[0098] In some embodiments, the antibody has a viscosity of about 4.6 cP at a concentration of about 180 mg / mL.

[0099] In some embodiments, the antibody has a turbidity (optical density (OD)) of about 0.5 or less at a concentration of about 150 mg / ml or greater in phosphate buffered saline (PBS) pH 7.4.

[0100] In some embodiments, the antibody has a turbidity (OD) of between about 0.25 and about 0.5 at a concentration of about 150 mg / ml to about 250 mg / ml.

[0101] In some embodiments, the antibody has a turbidity (OD) of about 0.38 at a concentration of about 200 mg / ml.

[0102] In some aspects, the antibody is monoclonal, human, humanized, or chimeric.

[0103] In some embodiments, the antibody is an antibody fragment that binds to IL-33.

[0104] In some embodiments, the antibody fragment is a Fab, Fab'-SH, Fv, scFv, or (Fab')2 fragment.

[0105] In some embodiments, the antibody fragment is a Fab.

[0106] In some embodiments, the antibody is a full-length antibody.

[0107] In some embodiments, the antibody is an IgG antibody.

[0108] In some embodiments, the IgG antibody is an IgG1 antibody.

[0109] In some embodiments, the IgG antibody is an IgG4 antibody.

[0110] In some embodiments, the antibody is a monospecific antibody.

[0111] In some embodiments, the antibody is a multispecific antibody.

[0112] In some embodiments, the antibody is a bispecific antibody.

[0113] In some embodiments, the bispecific antibody comprises a second binding domain that binds to a second biological molecule, wherein the second biological molecule is interleukin-13 (IL-13), interleukin-4 (IL-4), interleukin-5 (IL-5), interleukin-17 (IL-17), factor D, HtrA1, VEGF, or a VEGF receptor.

[0114] In another aspect, provided herein is an isolated nucleic acid encoding any one of the antibodies disclosed herein, or a set of isolated nucleic acids which together encode the antibodies.

[0115] In another aspect, provided herein is a vector or set of vectors comprising any of the isolated nucleic acids or set of isolated nucleic acids disclosed herein.

[0116] In another aspect, provided herein is a host cell comprising any one of the vectors or set of vectors disclosed herein.

[0117] In some embodiments, the host cell is a mammalian cell.

[0118] In some embodiments, the mammalian cell is a Chinese hamster ovary (CHO) cell.

[0119] In some embodiments, the host cell is a prokaryotic cell.

[0120] In some embodiments, the prokaryotic cell is E. coli.

[0121] In another aspect, provided herein is a method for producing an antibody that specifically binds to IL-33, the method comprising culturing in a medium any one of the host cells disclosed herein.

[0122] In some aspects, the method further comprises recovering the antibody from the host cell or culture medium.

[0123] In another aspect, provided herein is a composition comprising any one of the antibodies disclosed herein.

[0124] In some embodiments, the composition further comprises a pharmaceutically acceptable carrier, excipient, or diluent.

[0125] In some embodiments, the composition is a pharmaceutical composition.

[0126] In some embodiments, the pharmaceutical composition further comprises an ST2 binding antagonist, a factor D binding antagonist, an HtrA1 binding antagonist, a VEGF antagonist, a tryptase-beta binding antagonist, a chemoattractant receptor-like molecule expressed on Th2 cells (CRTH2) binding antagonist, an interleukin-13 (IL-13) binding antagonist, an interleukin-17 (IL-17) binding antagonist, a JAK1 antagonist, and / or an interleukin-5 (IL-5) binding antagonist.

[0127] In some embodiments, the pharmaceutical composition comprises a Factor D binding antagonist.

[0128] In some embodiments, the Factor D binding antagonist is an anti-Factor D antibody or antigen-binding fragment thereof.

[0129] In some embodiments, the pharmaceutical composition comprises an HtrA1 binding antagonist.

[0130] In some embodiments, the HtrA1 binding antagonist is an anti-HtrA1 antibody or an antigen-binding fragment thereof.

[0131] In some embodiments, the pharmaceutical composition comprises a VEGF antagonist.

[0132] In some embodiments, the VEGF antagonist is an anti-VEGF antibody or antigen-binding fragment thereof.

[0133] In some embodiments, the antibody concentration is from about 1 mg / mL to about 400 mg / mL.

[0134] In some embodiments, the antibody concentration is from about 150 mg / mL to about 250 mg / mL.

[0135] In some embodiments, the antibody concentration is from about 175 mg / mL to about 225 mg / mL.

[0136] In some embodiments, the antibody concentration is about 200 mg / mL.

[0137] In another aspect, provided herein is any one of the antibodies disclosed herein or any one of the compositions disclosed herein for use as a medicament.

[0138] In another aspect, provided herein is any one of the antibodies disclosed herein or any one of the compositions disclosed herein for use in treating an IL-33-mediated disorder.

[0139] In some embodiments, the IL-33-mediated disorder is an ocular disorder, an inflammatory condition, an immune disorder, a fibrotic disorder, an eosinophilic disorder, an infection, pain, a central nervous system disorder, or a solid tumor.

[0140] In some embodiments, the ocular disorder is age-related macular degeneration (AMD), ocular retinopathy, polypoidal choroidal vasculopathy (PCV), diabetic macular edema, dry eye disease, Behcet's disease, retinal detachment, glaucoma, uveitis, retinitis pigmentosa, Leber's congenital amaurosis, Stargardt's disease, traumatic eye injury, or conjunctivitis.

[0141] In some embodiments, the AMD is geographic atrophy (GA), wet AMD, or dry AMD.

[0142] In some embodiments, the AMD is GA.

[0143] In some embodiments, the AMD is intermediate AMD or advanced AMD.

[0144] In some embodiments, the ocular retinopathy is diabetic retinopathy (DR) or retinopathy of prematurity (ROP).

[0145] In some embodiments, the ocular retinopathy is high altitude DR.

[0146] In some aspects, the conjunctivitis is infectious conjunctivitis or non-infectious conjunctivitis.

[0147] In some embodiments, the conjunctivitis is allergic conjunctivitis.

[0148] In some embodiments, the inflammatory condition is asthma, sepsis, septic shock, atopic dermatitis, allergic rhinitis, rheumatoid arthritis, or chronic obstructive pulmonary disease (COPD).

[0149] In some embodiments, the immune disorder is asthma, rheumatoid arthritis, allergy, anaphylaxis, anaphylactic shock, allergic rhinitis, psoriasis, inflammatory bowel disease (IBD), Crohn's disease, diabetes, or liver disease.

[0150] In some embodiments, the fibrotic disease is idiopathic pulmonary fibrosis (IPF).

[0151] In some embodiments, the eosinophilic disorder is eosinophil-associated gastrointestinal disorder (EGID).

[0152] In some embodiments, the EGID is eosinophilic esophagitis.

[0153] In some embodiments, the infection is a helminth infection, a protozoan infection, or a viral infection.

[0154] In some embodiments, the protozoan infection is a Leishmania major infection.

[0155] In some embodiments, the viral infection is a respiratory syncytial virus (RSV) infection or an influenza infection.

[0156] In some embodiments, the pain is inflammatory pain.

[0157] In some embodiments, the central nervous system disorder is Alzheimer's disease.

[0158] In some aspects, the solid tumor is a breast tumor, a colon tumor, a prostate tumor, a lung tumor, a kidney tumor, a liver tumor, a pancreatic tumor, a stomach tumor, an intestinal tumor, a brain tumor, a bone tumor, and a skin tumor.

[0159] In some embodiments, the antibody or composition is used in combination with an ST2 binding antagonist, a Factor D binding antagonist, an HtrA1 binding antagonist, a VEGF antagonist, a tryptase-beta binding antagonist, a CRTH2 binding antagonist, an IL-13 binding antagonist, an IL-17 binding antagonist, a JAK1 antagonist, and / or an IL-5 binding antagonist.

[0160] In some embodiments, the antibody or composition is used in combination with a Factor D binding antagonist.

[0161] In some embodiments, the Factor D binding antagonist is an anti-Factor D antibody or antigen-binding fragment thereof.

[0162] In some embodiments, the antibody or composition is used in combination with an HtrA1 factor binding antagonist.

[0163] In some embodiments, the HtrA1 binding antagonist is an anti-HtrA1 antibody or an antigen-binding fragment thereof.

[0164] In some embodiments, the antibody or composition is used in combination with a VEGF factor binding antagonist.

[0165] In some embodiments, the VEGF antagonist is an anti-VEGF antibody or antigen-binding fragment thereof.

[0166] In another aspect, provided herein is the use of any one of the antibodies disclosed herein or any one of the compositions disclosed herein in the manufacture of a medicament for treating an IL-33-mediated disorder.

[0167] In some embodiments, the IL-33-mediated disorder is an ocular disorder, an inflammatory condition, an immune disorder, a fibrotic disorder, an eosinophilic disorder, an infection, pain, a central nervous system disorder, or a solid tumor.

[0168] In some embodiments, the ocular disorder is AMD, ocular retinopathy, PCV, diabetic macular edema, dry eye disease, Behcet's disease, retinal detachment, glaucoma, uveitis, retinitis pigmentosa, Leber's congenital amaurosis, Stargardt's disease, traumatic eye injury, or conjunctivitis.

[0169] In some embodiments, the AMD is GA, wet AMD, or dry AMD.

[0170] In some embodiments, the AMD is GA.

[0171] In some embodiments, the AMD is intermediate AMD or advanced AMD.

[0172] In some embodiments, the ocular retinopathy is DR or ROP.

[0173] In some embodiments, the ocular retinopathy is high altitude DR.

[0174] In some aspects, the conjunctivitis is infectious conjunctivitis or non-infectious conjunctivitis.

[0175] In some embodiments, the conjunctivitis is allergic conjunctivitis.

[0176] In some embodiments, the inflammatory condition is asthma, sepsis, septic shock, atopic dermatitis, allergic rhinitis, rheumatoid arthritis, or COPD.

[0177] In some embodiments, the immune disorder is asthma, rheumatoid arthritis, allergy, anaphylaxis, anaphylactic shock, allergic rhinitis, psoriasis, IBD, Crohn's disease, diabetes, or liver disease.

[0178] In some embodiments, the fibrotic disease is IPF.

[0179] In some embodiments, the eosinophilic disorder is EGID.

[0180] In some embodiments, the EGID is eosinophilic esophagitis.

[0181] In some embodiments, the infection is a helminth infection, a protozoan infection, or a viral infection.

[0182] In some embodiments, the protozoan infection is a Leishmania major infection.

[0183] In some embodiments, the viral infection is a RSV infection or an influenza infection.

[0184] In some embodiments, the pain is inflammatory pain.

[0185] In some embodiments, the central nervous system disorder is Alzheimer's disease.

[0186] In some aspects, the solid tumor is a breast tumor, a colon tumor, a prostate tumor, a lung tumor, a kidney tumor, a liver tumor, a pancreatic tumor, a stomach tumor, an intestinal tumor, a brain tumor, a bone tumor, and a skin tumor.

[0187] In some embodiments, the medicament is formulated for use in combination with an ST2 binding antagonist, a Factor D binding antagonist, an HtrA1 binding antagonist, a VEGF antagonist, a tryptase-beta binding antagonist, a CRTH2 binding antagonist, an IL-13 binding antagonist, an IL-17 binding antagonist, a JAK1 antagonist, and / or an IL-5 binding antagonist.

[0188] In some embodiments, the medicament is formulated for use in combination with a Factor D binding antagonist.

[0189] In some embodiments, the Factor D binding antagonist is an anti-Factor D antibody or antigen-binding fragment thereof.

[0190] In some embodiments, the medicament is formulated for use in combination with an HtrA1 binding antagonist.

[0191] In some embodiments, the HtrA1 binding antagonist is an anti-HtrA1 antibody or an antigen-binding fragment thereof.

[0192] In some embodiments, the medicament is formulated for use in combination with a VEGF antagonist.

[0193] In some embodiments, the VEGF antagonist is an anti-VEGF antibody or antigen-binding fragment thereof.

[0194] In another aspect, provided herein is a method of treating an IL-33-mediated disorder in a subject in need thereof, comprising administering to the subject a therapeutically effective amount of any one of the antibodies disclosed herein or any one of the compositions disclosed herein.

[0195] In some embodiments, the IL-33-mediated disorder is an ocular disorder, an inflammatory condition, an immune disorder, a fibrotic disorder, an eosinophilic disorder, an infection, pain, a central nervous system disorder, or a solid tumor.

[0196] In some embodiments, the ocular disorder is AMD, ocular retinopathy, PCV, diabetic macular edema, dry eye disease, Behcet's disease, retinal detachment, glaucoma, uveitis, retinitis pigmentosa, Leber's congenital amaurosis, Stargardt's disease, traumatic eye injury, or conjunctivitis.

[0197] In some embodiments, the AMD is GA, wet AMD, or dry AMD.

[0198] In some embodiments, the AMD is GA.

[0199] In some embodiments, the AMD is intermediate AMD or advanced AMD.

[0200] In some embodiments, the ocular retinopathy is DR or ROP.

[0201] In some embodiments, the ocular retinopathy is high altitude DR.

[0202] In some aspects, the conjunctivitis is infectious conjunctivitis or non-infectious conjunctivitis.

[0203] In some embodiments, the conjunctivitis is allergic conjunctivitis.

[0204] In some embodiments, the inflammatory condition is asthma, sepsis, septic shock, atopic dermatitis, allergic rhinitis, rheumatoid arthritis, or COPD.

[0205] In some embodiments, the immune disorder is asthma, rheumatoid arthritis, allergies, anaphylaxis, anaphylactic shock, allergic rhinitis, psoriasis, IBD, Crohn's disease, diabetes, and liver disease.

[0206] In some embodiments, the fibrotic disease is IPF.

[0207] In some embodiments, the eosinophilic disorder is EGID.

[0208] In some embodiments, the EGID is eosinophilic esophagitis.

[0209] In some embodiments, the infection is a helminth infection, a protozoan infection, or a viral infection.

[0210] In some embodiments, the protozoan infection is a Leishmania major infection.

[0211] In some embodiments, the viral infection is a RSV infection or an influenza infection.

[0212] In some embodiments, the pain is inflammatory pain.

[0213] In some aspects, the solid tumor is a breast tumor, a colon tumor, a prostate tumor, a lung tumor, a kidney tumor, a liver tumor, a pancreatic tumor, a stomach tumor, an intestinal tumor, a brain tumor, a bone tumor, and a skin tumor.

[0214] In some embodiments, the method further includes administering to the subject an ST2 binding antagonist, a Factor D binding antagonist, an HtrA1 binding antagonist, a VEGF antagonist, a tryptase-beta binding antagonist, a CRTH2 binding antagonist, an IL-13 binding antagonist, an IL-17 binding antagonist, a JAK1 antagonist, and / or an IL-5 binding antagonist.

[0215] In some embodiments, the method further comprises administering to the subject a Factor D binding antagonist.

[0216] In some embodiments, the Factor D binding antagonist is an anti-Factor D antibody or antigen-binding fragment thereof.

[0217] In some embodiments, the method further comprises administering to the subject an HtrA1 binding antagonist.

[0218] In some embodiments, the HtrA1 binding antagonist is an anti-HtrA1 antibody or an antigen-binding fragment thereof.

[0219] In some embodiments, the method further comprises administering to the subject a VEGF antagonist.

[0220] In some embodiments, the VEGF antagonist is an anti-VEGF antibody or antigen-binding fragment thereof.

[0221] In another aspect, provided herein is a method for treating GA in a subject in need thereof, comprising administering to the subject a therapeutically effective amount of any one of the antibodies disclosed herein or any one of the compositions disclosed herein.

[0222] In some embodiments, the antibody is a Fab fragment.

[0223] In some aspects, the antibody or composition is administered intravitreally, ophthalmically, intraocularly, juxtasclerally, subtenonally, suprachoroidally, topically, intravenously, intramuscularly, intradermally, transcutaneously, intra-arterially, intraperitoneally, intralesionally, intracranially, intra-articularly, intraprostatically, intrathoracically, intratracheally, intrathecally, intranasally, intravaginally, intrarectally, topically, intratumorally, intraperitoneally, peritoneally, intraventricularly, subcutaneously, subconjunctivally, intravesically, mucosally, intrapericardially, intraumbilically, intraorbitally, orally, transdermally, by inhalation, by injection, by eye drops, by implantation, by infusion, by continuous infusion, by local perfusion bathing directly in target cells, by catheter, by lavage, in a cream, or in a lipid composition.

[0224] In some aspects, the antibody or composition is administered intravitreally, ophthalmically, intraocularly, juxtasclerally, subtenonally, suprachoroidally, or topically.

[0225] In some aspects, the antibody or composition is administered intravitreally by injection.

[0226] In some aspects, the antibody or composition is administered topically via eye drops or ointment.

[0227] In some aspects, the antibody or composition is administered by a port delivery device.

[0228] In some embodiments, the subject is a human. [Brief explanation of the drawings]

[0229] [Figure 1A-1B] Figures 1A and 1B show sequence alignments of the heavy chain variable region (VH) and light chain variable region (VL) sequences of the 1E1 hybridoma and 1E1v8 anti-IL-33 antibody clones. Complementarity-determining region (CDR) sequences, as defined by Kabat, are underlined. [Figure 2A-2B] Figures 2A and 2B are sequence alignments of the VH and VL sequences of the indicated anti-IL-33 antibody clones. CDR sequences according to the Kabat definition are underlined. [Figure 3A] FIG. 3A is a network plot showing the relationship between clones or bins of anti-IL-33 antibody clones based on blocking activity. [Figure 3B] FIG. 3B is a heat map showing the relationship between clones or bins of anti-IL-33 antibody clones based on blocking activity. [Figure 3C-3E] Figures 3C-3E are a series of graphs showing the results of epitope binning using surface plasmon resonance (SPR). The graphs show normalized response as a function of time. DETAILED DESCRIPTION OF THE INVENTION

[0230] I. Definition The term "about" as used herein refers to a normal error range for the respective value, which would be readily understood by one of ordinary skill in the art. Reference to "about" a value or parameter herein includes (and describes) embodiments that are directed to the value or parameter itself.

[0231] For purposes herein, an "acceptor human framework" is a framework that comprises the amino acid sequence of a light chain variable domain (VL) framework or a heavy chain variable domain (VH) framework derived from a human immunoglobulin framework or a human consensus framework, as defined below. An acceptor human framework "derived from" a human immunoglobulin framework or a human consensus framework may comprise the same amino acid sequence or may contain amino acid sequence changes. In some embodiments, the number of amino acid changes is 10 or less, 9 or less, 8 or less, 7 or less, 6 or less, 5 or less, 4 or less, 3 or less, or 2 or less. In some embodiments, the VL acceptor human framework is identical in sequence to the VL human immunoglobulin framework sequence or the human consensus framework sequence.

[0232] "Affinity" refers to the strength of the sum of non-covalent interactions between a single binding site of a molecule (e.g., an antibody) and its binding partner (e.g., an antigen). Unless otherwise indicated, as used herein, "binding affinity" refers to the intrinsic binding affinity that reflects a 1:1 interaction between members of a binding pair (e.g., an antibody and an antigen). The affinity of a molecule X for its partner Y is generally determined by the dissociation constant (K D ) Affinity can be measured by common methods known in the art, including those described herein. Specific illustrative examples and exemplary embodiments for measuring binding affinity are described below.

[0233] An "affinity matured" antibody is one with one or more alterations in one or more HVRs and / or framework regions that result in improved affinity of the antibody for antigen compared to a parent antibody lacking those alteration(s). Preferred affinity matured antibodies will have nanomolar or even picomolar affinity for the target antigen. Affinity matured antibodies are produced by procedures known in the art. For example, Marks et al. Bio / Technology 10:779-783, 1992, describes affinity maturation by VH and VL domain shuffling. Random mutagenesis of HVR and / or framework residues has been described by Barbas et al. Proc. Natl. Acad. Sci. USA 91:3809-3813, 1994; Schier et al. Gene 169:147-155, 1995; Yelton et al. J. Immunol. 155:1994-2004, 1995; Jackson et al. J. Immunol. 154(7):3310-3319, 1995; and Hawkins et al. J. Mol. Biol. 226:889-896, 1992.

[0234] The term "antibody" is used herein in the broadest sense and encompasses a variety of antibody structures, including, but not limited to, monoclonal antibodies, polyclonal antibodies, multispecific antibodies (e.g., bispecific antibodies, including anti-IL-33 / anti-IL-13 bispecific antibodies), and antibody fragments, so long as they exhibit the desired antigen-binding activity.

[0235] As used herein, the term "interleukin-33 (IL-33)" refers to any native IL-33 from any vertebrate source, including mammals such as primates (e.g., humans and cynomolgus monkeys) and rodents (e.g., mice and rats), unless otherwise specified. IL-33 has also been referred to in the art as nuclear factor of high endothelial venules (NF-HEV; see, e.g., Baekkevold et al. Am. J. Pathol. 163(1):69-79, 2003), DVS27, C9orf26), DVS27, C9orf26, and interleukin-1 family member 11 (IL-1F11). The term encompasses "full-length," unprocessed IL-33 and any form of IL-33 resulting from intracellular processing. Human full-length, unprocessed IL-33 contains 270 amino acids (aa), and IL-33 1-270 Processed forms of human IL-33 include, for example, IL-33 95-270 , IL-33 99-270 , IL-33 109-270 , IL-33 112-270 , IL-33 1-178 , and IL-33 179-270 (Lefrancais et al. Proc. Natl. Acad. Sci. 109(5):1673-1678, 2012 and Martin, Semin. Immunol. 25:449-457, 2013). In some embodiments, processed forms of human IL-33, e.g., IL-33 95-270 , IL-33 99-270 , IL-33 109-270IL-33, or other forms processed by proteases such as calpain, proteinase 3, neutrophil elastase, and cathepsin G, may have increased biological activity compared to full-length IL-33. The term also encompasses naturally occurring variants of IL-33, such as splice variants (e.g., the constitutively active splice variant spIL-33 lacking exon 3; Hong et al. J. Biol. Chem. 286(22):20078-20086, 2011) or allelic variants. IL-33 may exist intracellularly (e.g., in the nucleus) or as a secreted cytokine form. The full-length IL-33 protein contains a helix-turn-helix DNA-binding motif containing a nuclear localization sequence (aa 1-75 of human IL-33) that includes a chromatin-binding motif (aa 40-58 of human IL-33). The processed and secreted form of IL-33 lacks these N-terminal motifs. The amino acid sequence of an exemplary human IL-33 can be found, for example, at UniProtKB accession number O95760.

[0236] "IL-33 axis" refers to nucleic acids (e.g., genes or mRNA transcribed from genes) or polypeptides involved in IL-33 signaling. For example, the IL-33 axis can include the ligand IL-33, receptors (e.g., ST2 and / or IL-1RAcP), adaptor molecules (e.g., MyD88), or proteins that associate with the receptor molecules and / or adaptor molecules (e.g., kinases such as interleukin-1 receptor-associated kinase 1 (IRAK1) and interleukin-1 receptor-associated kinase 4 (IRAK4), or E3 ubiquitin ligases such as TNF receptor-associated factor 6 (TRAF6)).

[0237] The terms "interleukin-1 receptor-like 1 (IL1RL1)" and "ST2," used interchangeably herein, refer to any native ST2 from any vertebrate source, including mammals such as primates (e.g., humans) and rodents (e.g., mice and rats), unless otherwise specified. ST2 is also referred to in the art as DER4, T1, and FIT-1. The term encompasses "full-length," unprocessed ST2 and any form of ST2 resulting from intracellular processing. At least four isoforms of ST2 are known in the art, including soluble (sST2, also known as IL1RL1-a) and transmembrane (ST2L, also known as IL1RL1-b) resulting from differential mRNA expression from a dual promoter system, as well as ST2V and ST2LV resulting from alternative splicing, as described below. The domain structure of ST2L includes three extracellular immunoglobulin-like C2 domains, a transmembrane domain, and a cytoplasmic Toll / interleukin-1 receptor (TIR) ​​domain. sST2 lacks the transmembrane and cytoplasmic domains contained within ST2L and contains a unique 9-amino acid (aa) C-terminal sequence (see, e.g., Kakkar et al. Nat. Rev. Drug Disc. 7:827-840, 2008). sST2 can function as a decoy receptor to inhibit soluble IL-33. The term also encompasses naturally occurring variants of ST2, such as splice variants (e.g., ST2V, which lacks the third immunoglobulin motif and has a unique hydrophobic tail, and ST2LV, which lacks the transmembrane domain of ST2L) or allelic variants (e.g., variants that are protective against asthma risk or confer asthma risk as described herein). The amino acid sequence of an exemplary human ST2 can be found, for example, as UniProtKB Accession No. Q01638. ST2 is part of the IL-33 receptor together with the co-receptor protein IL-1RAcP.Binding of IL-33 to ST2 and the co-receptor interleukin-1 receptor accessory protein (IL-1RAcP) forms a 1:1:1 ternary signaling complex to promote downstream signaling (see Figure 1A) (see, e.g., Lingel et al. Structure 17(10):1398-1410, 2009, and Liu et al. Proc. Natl. Acad. Sci. 110(37):14918-14924, 2013).

[0238] The terms "anti-IL-33 antibody," "antibody that binds IL-33," and "antibody that specifically binds IL-33" refer to an antibody that can bind IL-33 with sufficient affinity such that the antibody is useful as a therapeutic and / or diagnostic agent in targeting IL-33. In one embodiment, the extent to which an anti-IL-33 antibody binds to an unrelated, non-IL-33 protein is less than about 10% of the binding of the antibody to IL-33, as measured, for example, by radioimmunoassay (RIA). In certain embodiments, an antibody that binds IL-33 has a dissociation constant (K D ) is ≦1 μM, ≦100 nM, ≦10 nM, ≦1 nM, ≦0.1 nM, ≦0.01 nM, or ≦0.001 nM (e.g., 10 -8 M or less, e.g., 10 -8 M~10 -13 M, e.g. 10 -9 M~10 -13 In certain embodiments, the anti-IL-33 antibody binds to an epitope of IL-33 that is conserved among IL-33 from different species.

[0239] An "antibody that binds to the same epitope" as a reference antibody refers to an antibody that inhibits the binding of the reference antibody to its antigen by 50% or more in a competition assay, and conversely, the reference antibody inhibits the binding of the antibody to its antigen by 50% or more in a competition assay. An exemplary competition assay is provided herein.

[0240] An "antibody fragment" comprises a portion of an intact antibody, preferably the antigen-binding or variable region of the intact antibody. Examples of antibody fragments include Fab, Fab', F(ab')2, and Fv fragments; diabodies; linear antibodies (see Example 2 of U.S. Pat. No. 5,641,870; Zapata et al., Protein Eng. 8(10):1057-1062, 1995); single-chain antibody molecules; and multispecific antibodies formed from antibody fragments.

[0241] Papain digestion of antibodies produces two identical antigen-binding fragments called "Fab" fragments and a residual "Fc" fragment, a designation reflecting its ability to crystallize readily. The Fab fragment contains the entire light chain and the variable region domain of the heavy chain (VH), and the first constant domain of one heavy chain (C). H 1). Pepsin treatment of an antibody yields a single large F(ab')2 fragment, roughly corresponding to two disulfide-linked Fab fragments, which have bivalent antigen-binding activity and are capable of cross-linking antigen. The Fab' fragment contains one or more cysteines from the antibody hinge region, and is capable of cross-linking antigen. H F(ab')2 antibody fragments differ from Fab fragments by having a few additional residues at the carboxy terminus of one domain. Fab'-SH is the designation used herein for Fab' in which the cysteine ​​residues of the constant domains bear free thiol groups. F(ab')2 antibody fragments originally were produced as pairs of Fab' fragments which have hinge cysteines between them. Other chemical couplings of antibody fragments are also known.

[0242] The term "Fc region" herein is used to define the C-terminal region of an immunoglobulin heavy chain containing at least a portion of the constant region. The term includes native-sequence Fc regions and variant Fc regions. In one embodiment, a human IgG heavy chain Fc region extends from Cys226, or from Pro230, to the carboxyl terminus of the heavy chain. However, the C-terminal lysine of the Fc region (Lys447) may or may not be present. Unless otherwise specified herein, the numbering of amino acid residues in the Fc region or constant region is according to the EU numbering system (also referred to as the EU index), as described in Kabat et al., Sequences of Proteins of Immunological Interest, 5th Ed. Public Health Service, National Institutes of Health, Bethesda, MD, 1991.

[0243] An "Fv" consists of a dimer of one heavy-chain and one light-chain variable domain in tight, non-covalent association. The folding of these two domains results in six hypervariable loops (three loops from each H and L chain) that provide the amino acid residues for antigen binding and confer antigen-binding specificity to the antibody. However, even a single variable domain (or half of an Fv containing only three antigen-specific Hs) has the ability to recognize and bind antigen, although often with lower affinity than the entire binding site.

[0244] A "single-chain Fv," also abbreviated as "sFv" or "scFv," is an antibody fragment comprising the VH and VL antibody domains connected in a single polypeptide chain. Preferably, the sFv polypeptide further comprises a polypeptide linker between the VH and VL domains that enables the sFv to form the desired structure for antigen binding. For a review of sFvs, see, e.g., The Pharmacology of Monoclonal Antibodies, vol. 113, Rosenburg and Moore eds., Springer-Verlag, New York, pp. 269-315, 1994.

[0245] The term "diabody" refers to small antibody fragments prepared by constructing sFv fragments (see previous paragraph) using a short linker (approximately 5-10 residues) between the VH and VL domains, thereby achieving interchain rather than intrachain pairing of the V domains, thereby creating a bivalent fragment, i.e., a fragment with two antigen-binding sites. Bispecific diabodies are heterodimers of two "crossover" sFv fragments in which the VH and VL domains of the two antibodies are present on different polypeptide chains. Diabodies are described in further detail, for example, in EP 404,097; WO 93 / 11161; and Hollinger et al., Proc. Natl. Acad. Sci. USA, 90:64446448 (1993).

[0246] "Binding domain" refers to a portion of a compound or molecule that specifically binds to a target epitope, antigen, ligand, or receptor. Binding domains include, but are not limited to, antibodies (e.g., monoclonal, polyclonal, recombinant, humanized, and chimeric antibodies), antibody fragments or portions thereof (e.g., Fab fragments, Fab'2, scFv antibodies, SMIPs, domain antibodies, diabodies, minibodies, scFv-Fc, affibodies, nanobodies, and antibody VH and / or VL domains), receptors, ligands, aptamers, and other molecules with identified binding partners.

[0247] A "blocking" or "antagonist" antibody is an antibody that inhibits or reduces the biological activity of the antigen to which it binds. Particular blocking or antagonist antibodies substantially or completely inhibit the biological activity of the antigen.

[0248] A "cell-based blocking assay" refers to an assay that can measure the ability of an antibody to inhibit or reduce the biological activity of an antigen to which the antibody binds. For example, a cell-based assay can be used to measure the concentration of an antibody required to inhibit a specific biological or biochemical function. In some embodiments, the half-maximal inhibitory concentration (IC50) and / or 90% inhibitory concentration (IC90) of an antibody (e.g., an anti-IL-33 antibody disclosed herein) are measured using a cell-based blocking assay. In some embodiments, a cell-based blocking assay is used to determine whether an antibody blocks the interaction between a ligand (e.g., IL-33) and its receptor (e.g., ST2 and / or co-receptor IL-1RAcP). An exemplary cell-based blocking assay for IL-33 is provided, for example, in Example 2B of U.S. Pat. No. 10,093,730. Further exemplary cell-based blocking assays for IL-33 are provided, for example, in Example 8 of U.S. Pat. No. 10,093,730, and include a primary natural killer (NK) cell assay and a primary basophil assay.

[0249] The "class" of an antibody refers to the type of constant domain or constant region possessed by its heavy chain. There are five major classes of antibodies: IgA, IgD, IgE, IgG, and IgM, and some of these can be further divided into subclasses (isotypes), e.g., IgG1, IgG2, IgG3, IgG4, IGA1, and IgA2. The heavy-chain constant domains that correspond to the different classes of immunoglobulins are called α, δ, ε, γ, and μ, respectively.

[0250] Antibody "effector functions" refer to the biological activities attributable to the Fc region of an antibody (a native sequence Fc region or an amino acid sequence variant Fc region) and vary depending on the antibody isotype. Examples of antibody effector functions include: C1q binding and complement-dependent cytotoxicity; Fc receptor binding; antibody-dependent cell-mediated cytotoxicity (ADCC); phagocytosis; down-regulation of cell surface receptors (e.g., B cell receptors); and B cell activation.

[0251] "Antibody-dependent cell-mediated cytotoxicity" or "ADCC" refers to a form of cytotoxicity in which secreted Ig bound to Fc receptors (FcRs) present on certain cytotoxic cells (e.g., natural killer (NK) cells, neutrophils, and macrophages) enables these cytotoxic effector cells to specifically bind to antigen-bearing target cells and subsequently kill the target cells by cytotoxicity. Antibodies "arm" the cytotoxic cells and are absolutely required for such killing. NK cells, the primary cells mediating ADCC, express only FcγRIII, whereas monocytes express FcγRI, FcγRII, and FcγRIII. FcR expression on hematopoietic cells is summarized in Table 3 on page 464 of Ravetch et al., Annu. Rev. Immunol. 9:457-492, 1991. To assess ADCC activity of a molecule of interest, an in vitro ADCC assay, such as that described in U.S. Patent No. 5,500,362 or 5,821,337, may be performed. Useful effector cells for such assays include peripheral blood mononuclear cells (PBMCs) and natural killer (NK) cells. Alternatively, or additionally, ADCC activity of a molecule of interest can be assessed in vivo, e.g., in an animal model such as that disclosed in Clynes et al. Proc. Natl. Acad. Sci. USA 95:652-656, 1998.

[0252] "Fc receptor" or "FcR" refers to a receptor that binds to the Fc region of an antibody. A preferred FcR is a native-sequence human FcR. Furthermore, a preferred FcR is one that binds IgG antibodies (gamma receptors), including receptors of the FcγRI, FcγRII, and FcγRIII subclasses, including allelic variants and alternatively spliced ​​forms of these receptors. FcγRII receptors include FcγRIIA (an "activating receptor") and FcγRIIB (an "inhibiting receptor"), which have similar amino acid sequences that differ primarily in their cytoplasmic domains. Activating receptor FcγRIIA contains an immunoreceptor tyrosine-based activation motif (ITAM) in its cytoplasmic domain. Inhibiting receptor FcγRIIB contains an immunoreceptor tyrosine-based inhibition motif (ITIM) in its cytoplasmic domain (see review M. in Daeron, Annu. Rev. Immunol. 15:203-234, 1997). FcRs are reviewed, for example, in Ravetch et al. Annu. Rev. Immunol. 9:457-492, 1991; Capel et al. Immunomethods 4:25-34, 1994; and de Haas et al. J. Lab. Clin. Med. 126:330-41, 1995. Other FcRs, including those yet to be identified, are encompassed herein by the term "FcR." This term also includes the neonatal receptor FcRn, which is responsible for the transfer of maternal IgG to the fetus (see, e.g., Guyer et al. J. Immunol. 117:587, 1976; and Kim et al. J. Immunol. 24:249, 1994).

[0253] A "human effector cell" is a leukocyte that expresses one or more FcRs and performs effector function. Preferably, the cell expresses at least FcγRIII and performs ADCC effector function. Examples of human leukocytes that mediate ADCC include peripheral blood mononuclear cells (PBMCs), natural killer (NK) cells, monocytes, cytotoxic T cells, and neutrophils, with PBMCs and NK cells being preferred. Effector cells can be isolated from natural sources, such as blood.

[0254] "Complement-dependent cytotoxicity" or "CDC" refers to the lysis of target cells in the presence of complement. Activation of the classical complement pathway is initiated by the binding of the first component of the complement system (C1q) to antibodies (of the appropriate subclass) bound to their cognate antigen. To assess complement activation, a CDC assay can be performed, e.g., as described in Gazzano-Santoro et al. J. Immunol. Methods 202:163, 1996.

[0255] An "epitope" is a portion of an antigen to which an antibody selectively binds. In the case of a polypeptide antigen, the epitope is generally a peptide portion of about 4 to 15 amino acid residues.

[0256] The terms "full-length antibody," "intact antibody," and "whole antibody" are used interchangeably herein to refer to an antibody having a heavy chain that has a structure substantially similar to a native antibody structure or that contains an Fc region as defined herein.

[0257] A "human antibody" is an antibody having an amino acid sequence that corresponds to that of an antibody produced by a human and / or made using any of the techniques for making human antibodies. This definition of human antibody specifically excludes humanized antibodies that comprise non-human antigen-binding residues.

[0258] A "human consensus framework" is a framework that represents the most commonly occurring amino acid residues in a selection of human immunoglobulin VL or VH framework sequences. Generally, the selection of human immunoglobulin VL or VH sequences is from a subgroup of variable domain sequences. Generally, the subgroup of sequences is a subgroup as in Kabat et al., Sequences of Proteins of Immunological Interest, Fifth Edition, NIH Publication 91-3242, Bethesda, MD, vols. 1-3, 1991. In one embodiment, for VL, the subgroup is subgroup kappa III or kappa IV as in Kabat et al., supra. In one embodiment, for VH, the subgroup is subgroup III as in Kabat et al., supra.

[0259] "Humanized" forms of non-human (e.g., rodent) antibodies are chimeric antibodies that contain minimal sequence derived from the non-human antibody. For the most part, humanized antibodies are human immunoglobulins (recipient antibody) in which residues from a hypervariable region of the recipient are replaced by residues from a hypervariable region of a non-human species (donor antibody) such as mouse, rat, rabbit, or non-human primate having the desired antibody specificity, affinity, and capacity. In some instances, framework region (FR) residues of the human immunoglobulin are replaced by corresponding non-human residues. Furthermore, humanized antibodies may comprise residues that are not found in the recipient antibody or the donor antibody. These modifications are made to further refine antibody performance. In general, humanized antibodies will comprise substantially all of at least one, and typically two, variable domains, with all or substantially all of the hypervariable loops corresponding to those of a non-human immunoglobulin and all or substantially all of the FRs being those of a human immunoglobulin sequence. The humanized antibody optionally also will comprise at least a portion of an immunoglobulin constant region (Fc), typically that of a human immunoglobulin. For further details, see Jones et al. Nature 321:522-525, 1986; Riechmann et al. Nature 332:323-329, 1988; and Presta, Curr. Op. Struct. Biol. 2:593-596, 1992.

[0260] An "immunoconjugate" is an antibody conjugated to one or more heterologous molecules, including, but not limited to, cytotoxic agents.

[0261] The term "isolated," when used to describe various antibodies disclosed herein, refers to an antibody that has been identified, separated, and / or recovered from the cell or cell culture in which it is expressed. Contaminant components of its natural environment are materials that would typically interfere with diagnostic or therapeutic uses for the polypeptide, and may include enzymes, hormones, and other proteinaceous or non-proteinaceous solutes. In some embodiments, the antibody is purified to greater than 95% or greater than 99% purity, as determined by electrophoretic (e.g., sodium dodecyl sulfate polyacrylamide gel electrophoresis (SDS-PAGE), isoelectric focusing (IEF), capillary electrophoresis) or chromatographic (e.g., ion exchange or reverse-phase HPLC) methods. For a review of methods for assessing antibody purity, see, e.g., Flatman et al. J. Chromatogr. B 848:79-87, 2007. In a preferred embodiment, the antibody is purified (1) sufficiently to obtain at least 15 residues of N-terminal or internal amino acid sequence using a spinning cup sequenator, or (2) to homogeneity by SDS-PAGE under non-reducing or reducing conditions using Coomassie blue or, preferably, silver stain. Isolated antibody includes antibody in situ within recombinant cells, since at least one component of the polypeptide's natural environment will not be present. Ordinarily, however, isolated polypeptide will be prepared by at least one purification step.

[0262] As used herein, the term "monoclonal antibody" refers to an antibody obtained from a population of substantially homogeneous antibodies, i.e., the individual antibodies comprising the population are identical and / or bind to the same epitope, except for variant antibodies (e.g., containing naturally occurring mutations or arising during production of the monoclonal antibody preparation) that may generally be present in minor amounts. In contrast to polyclonal antibody preparations, which typically include different antibodies directed against different determinants (epitopes), each monoclonal antibody of a monoclonal antibody preparation is directed against a single determinant on an antigen. Thus, the modifier "monoclonal" indicates the character of the antibody as being obtained from a substantially homogeneous antibody population and should not be construed as requiring production of the antibody by any particular method. For example, monoclonal antibodies used in accordance with the present invention can be produced by a variety of techniques, including, but not limited to, hybridoma methods, recombinant DNA methods, phage display methods, and methods utilizing transgenic animals containing all or part of the human immunoglobulin loci; such methods and other exemplary methods for producing monoclonal antibodies are described herein.

[0263] The term "multispecific antibody" is used in the broadest sense and specifically covers antibodies comprising a heavy chain variable domain (VH) and a light chain variable domain (VL) in which the VH-VL unit has polyepitopic specificity (i.e., can bind to two different epitopes on one biological molecule or each epitope on a different biological molecule). Such multispecific antibodies include, but are not limited to, full-length antibodies, antibodies with two or more VL and VH domains, antibody fragments such as Fab, Fv, dsFv, scFv, diabodies, bispecific diabodies, and triabodies, and covalently or non-covalently linked antibody fragments. "Polyepitopic specificity" refers to the ability to specifically bind to two or more different epitopes on the same or different target(s). "Bispecificity" or "dual specificity" refers to the ability to specifically bind to two different epitopes on the same or different target(s). However, in contrast to bispecific antibodies, diabodies have two antigen-binding arms with identical amino acid sequences, with each Fab arm capable of recognizing two antigens. Bispecificity allows an antibody to interact with two different antigens with high affinity as a single Fab or IgG molecule. According to one embodiment, an IgG1-type multispecific antibody binds to each epitope with an affinity of 5 μM to 0.001 pM, 3 μM to 0.001 pM, 1 μM to 0.001 pM, 0.5 μM to 0.001 pM, or 0.1 μM to 0.001 pM. "Monospecific" refers to the ability to bind to only one epitope.

[0264] As used herein, the term "knobs-into-holes" or "KnH" technology refers to a technique for directing pairing of two polypeptides in vitro or in vivo by introducing a protuberance (knob) into one polypeptide and a cavity (hole) into the other polypeptide at the interface where they interact. For example, KnH has been introduced into the Fc:Fc binding interface, the CL:CH1 interface, or the VH / VL interface of an antibody (see, e.g., U.S. Patent Application Publication No. 2011 / 0287009, U.S. Patent Application Publication No. 2007 / 0178552, WO 96 / 027011, WO 98 / 050431, and Zhu et al., Protein Science 6:781-788, 1997). In some embodiments, KnH drives pairing of two different heavy chains together during the production of multispecific antibodies. For example, multispecific antibodies with KnH in their Fc region may further comprise a single variable domain linked to each Fc region, or may further comprise a different heavy chain variable domain paired with a similar or different light chain variable domain. KnH technology can also be used to pair two different receptor extracellular domains together, or any other polypeptide sequence containing different target recognition sequences (including, for example, affibodies, peptibodies, and other Fc fusions).

[0265] As used herein, the term "knob mutation" refers to a mutation that introduces a protuberance (knob) into a polypeptide at the interface where the polypeptide interacts with another polypeptide. In some embodiments, the other polypeptide has a hole mutation (see, e.g., U.S. Patent Nos. 5,731,168; 5,807,706; 5,821,333; 7,695,936; and 8,216,805, each of which is incorporated by reference in its entirety).

[0266] As used herein, the term "hole mutation" refers to a mutation that introduces a cavity (hole) into a polypeptide at the interface where the polypeptide interacts with another polypeptide. In some embodiments, the other polypeptide has a knob mutation (see, e.g., U.S. Patent Nos. 5,731,168; 5,807,706; 5,821,333; 7,695,936; and 8,216,805, each of which is incorporated by reference in its entirety).

[0267] A "naked antibody" refers to an antibody that is not conjugated to a heterologous moiety (e.g., a cytotoxic moiety) or radiolabel. The naked antibody may be present in a pharmaceutical composition.

[0268] With respect to the binding of an antibody to a target molecule, the term "specific binding" of, or "specifically binds to," or "is specific for," a particular polypeptide or epitope on a particular polypeptide target means binding that is measurably different from non-specific interactions. Specific binding can be measured, for example, by determining the binding of a molecule relative to the binding of a control molecule. For example, specific binding can be determined by competition with a control molecule that is similar to the target, e.g., an excess of unlabeled target. In this case, specific binding is indicated when the binding of the labeled probe is competitively inhibited by an excess of unlabeled target. As used herein, the term "specific binding" of, or "specifically binds to," or "is specific for," a particular polypeptide or epitope on a particular polypeptide target refers to binding that is measurably different from non-specific interactions. -4 M or less, or 10 -5 M or less, or 10 -6 M or less, or 10 -7 M or less, or 10 -8 M or less, or 10 -9 M or less, or 10 -10 M or less, or 10 -11 M or less, or 10 -12 K against targets less than or equal to M D , or 10 -4 M~10-6 M or 10 -6 M~10 -10 M or 10 -7 M~10 -9 K in the M range D As will be appreciated by those skilled in the art, affinity and K D The values ​​are inversely correlated: a high affinity for the antigen corresponds to a low K D In one embodiment, the term "specific binding" refers to binding when a molecule binds to a particular polypeptide or epitope on a particular polypeptide without substantially binding to any other polypeptides or polypeptide epitopes.

[0269] The term "variable" refers to the fact that certain segments of the variable domain differ extensively in sequence among antibodies. The variable, or "V," domain mediates antigen binding and defines the specificity of a particular antibody for its particular antigen. However, variability is not uniformly distributed across the 110-amino acid span of the variable domain. Instead, the V region consists of relatively invariant stretches of 15-30 amino acids called framework regions (FRs), separated by short regions of extreme variability called "hypervariable regions," each 9-12 amino acids long. Naturally occurring heavy and light chain variable domains each contain four FRs that predominantly adopt a beta-sheet configuration connected by three hypervariable regions, which form loops that connect, and in some cases, form part of, the beta-sheet structure. The hypervariable regions in each chain are held together in close proximity by the FRs and, together with the hypervariable regions from the other chain, contribute to the formation of the antigen-binding site of antibodies (see Kabat et al., supra). Thus, the HVR and FR sequences generally appear in VH (or VL) in the following order: FR1-H1(L1)-FR2-H2(L2)-FR3-H3(L3)-FR4. The constant domains are not involved directly in binding an antibody to an antigen, but exhibit various effector functions, such as participation of the antibody in antibody-dependent cellular cytotoxicity (ADCC).

[0270] As used herein, the terms "hypervariable region," "HVR," or "HV" refer to the region of an antibody variable domain that is hypervariable in sequence and / or forms structurally defined loops. Antibodies typically contain six HVRs: three in the VH (H1, H2, and H3) and three in the VL (L1, L2, and L3). In natural antibodies, H3 and L3 exhibit the highest diversity of the six HVRs, and H3 in particular is thought to play a unique role in conferring superior specificity to antibodies. See, e.g., Xu et al., Immunity 13:37-45 (2000); Johnson and Wu, in Methods in Molecular Biology 248:125 (Lo, ed., Human Press, Totowa, NJ, 2003). In fact, naturally occurring camelid antibodies consisting only of heavy chains are functional and stable in the absence of light chains. See, e.g., Hamers-Casterman et al., Nature 363:446-448 (1993); Sheriff et al., Nature Struct. Biol. 3:733-736 (1996).

[0271] Several HVR delineations are used and encompassed herein. The Kabat Complementarity Determining Regions (CDRs) are based on sequence variability and are the most commonly used (Kabat et al., Sequences of Proteins of Immunological Interest, 5th Ed. Public Health Service, National Institutes of Health, Bethesda, Md. (1991)). Chothia instead refers to the location of structural loops (Chothia and Lesk J. Mol. Biol. 196:901-917 (1987)). The AbM HVRs represent a compromise between the Kabat HVRs and the Chothia structural loops and are used by Oxford Molecular's AbM antibody modeling software. The "contact" HVRs are based on analysis of available complex crystal structures. Residues from each of these HVRs are shown below.

[0272] TIFF2026031968000001.tif42170

[0273] HVRs may include the following "extended HVRs": 24-36 or 24-34 (L1), 46-56 or 50-56 (L2) and 89-97 or 89-96 (L3) in the VL, and 26-35 (H1), 50-65 or 49-65 (H2) and 93-102, 94-102, or 95-102 (H3) in the VH. The variable domain residues are numbered according to Kabat et al. (see above) for each of these definitions.

[0274] "Framework" or "FR" residues are those variable domain residues other than the HVR residues as herein defined.

[0275] The terms "Kabat variable domain residue numbering" or "Kabat amino acid position numbering," and variations thereof, refer to the numbering system used for the heavy or light chain variable domains of the compilation of antibodies in Kabat et al. (supra). Using this numbering system, the actual linear amino acid sequence may contain fewer or additional amino acids corresponding to a shortening of, or insertion into, the FRs or HVRs of the variable domain. For example, a heavy chain variable domain may contain a single amino acid insertion after residue 52 of H2 (residue 52a according to Kabat) and inserted residues after heavy chain FR residue 82 (e.g., residues 82a, 82b, and 82c, etc. according to Kabat). The Kabat numbering of residues can be determined for a given antibody by aligning the antibody's sequence with the "standard" Kabat numbered sequence at the regions of homology.

[0276] The Kabat numbering system is generally used when referring to residues within the variable domain (approximately residues 1-107 of the light chain and residues 1-113 of the heavy chain) (e.g., Kabat et al., supra). The "EU numbering system" or "EU index" is generally used when referring to residues in an immunoglobulin heavy chain constant region (e.g., the EU index reported in Kabat et al., supra). The "EU index in Kabat" refers to the residue numbering of the human IgG1 EU antibody. Unless otherwise indicated herein, references to residue numbers in the variable domain of an antibody refer to residue numbering according to the Kabat numbering system. Unless otherwise indicated herein, references to residue numbers in the constant domain of an antibody refer to residue numbering according to the EU numbering system (see, e.g., U.S. Provisional Application No. 60 / 640,323, figures for EU numbering).

[0277] As used herein, "administering" refers to a method of providing a subject with a dosage of a compound (e.g., an anti-IL-33 antibody provided herein or a nucleic acid encoding an anti-IL-33 antibody provided herein) or composition (e.g., a pharmaceutical composition, e.g., a pharmaceutical composition comprising an anti-IL-33 antibody provided herein). The compositions used in the methods described herein can be administered, for example, intravitreally, intramuscularly, intravenously, intradermally, transcutaneously, intraarterially, intraperitoneally, intralesionally, intracranially, intraarticularly, intraprostatically, intrapleurally, intratracheally, intrathecally, intranasally, intravaginally, intrarectally, topically, intratumorally, peritoneally, subcutaneously, subconjunctivally, intravesically, mucosally, intrapericardially, intraumbilically, intraocularly, intraorbitally, orally, topically, transdermally, periocularly, conjunctivally, subtenonally, intracamerally, subretinally, retrobulbarly, intracanalicularly, by inhalation, injection, implantation, infusion, continuous infusion, by localized perfusion directly bathing target cells, by catheter, by perfusion, in a cream, or in a lipid composition. The compositions used in the methods described herein can also be administered systemically or locally. The administration method can vary depending on various factors (e.g., the compound or composition to be administered and the severity of the condition, disease, or disorder to be treated).

[0278] The term "asthma," as used herein, refers to a disorder characterized by variable and recurrent symptoms, reversible airway obstruction (e.g., by bronchodilators), and bronchial hyperresponsiveness, which may or may not be associated with underlying inflammation. Asthma can therefore be inflammatory / inflamed asthma or non-inflammatory / non-inflamed asthma. Examples of asthma include allergic asthma, exercise-induced asthma, aspirin-sensitive / exacerbated asthma, atopic asthma, severe asthma, mild asthma, moderate-to-severe asthma, corticosteroid-naive asthma, chronic asthma, corticosteroid-resistant asthma, corticosteroid-refractory asthma, newly diagnosed untreated asthma, smoking-related asthma, corticosteroid-uncontrolled asthma, and other asthma mentioned in Bousquet et al. J. Allergy Clin. Immunol. 126(5):926-938, 2010.

[0279] A "disorder" or "disease" is any condition that would benefit from treatment with the antibodies provided herein. For example, the disorder can be an IL-33-mediated disorder. This includes chronic and acute disorders or diseases, including pathological conditions that predispose a mammal to the disorder in question. Examples of disorders treated herein include IL-33-mediated disorders (e.g., asthma, allergic rhinitis, atopic dermatitis, and fibrosis (e.g., pulmonary fibrosis, e.g., idiopathic pulmonary fibrosis)).

[0280] The term "IL-33-mediated disorder," as used herein, refers to any disorder or condition mediated by or associated with the IL-33 axis. In some embodiments, an IL-33-mediated disorder is associated with excessive IL-33 levels or activity, which may result in atypical symptoms due to local and / or systemic IL-33 levels or activity in the body. Exemplary IL-33-mediated disorders include ocular disorders, inflammatory conditions, immune disorders, fibrotic disorders, eosinophilic disorders, infections, pain, central nervous system disorders, and solid tumors. IL-33-mediated disorders are described, for example, in Liew et al. Nature Reviews Immunology 10:103-110, 2010, which is incorporated herein by reference in its entirety.

[0281] The term "ocular disorder" as used herein includes any ocular disorder (interchangeably referred to herein as "ocular condition") associated with pathological neovascularization and / or atrophy. Ocular disorders can be characterized by altered or dysregulated proliferation and / or infiltration of new blood vessels into structures of ocular tissues, such as the retina or cornea. Ocular disorders can be characterized by atrophy of retinal tissues (photoreceptors and the underlying retinal pigment epithelium (RPE) and choriocapillaris). Non-limiting ocular disorders include, for example, AMD (e.g., wet AMD, dry AMD, intermediate AMD, advanced AMD, and geographic atrophy (GA)), macular degeneration, macular edema, diabetic macular edema (DME) (e.g., focal, non-central DME, and diffuse, centrally involved DME), retinopathies, diabetic retinopathy (DR) (e.g., proliferative DR (PDR), non-proliferative DR (NPDR), and high altitude DR), other ischemia-related retinopathies, ROP, retinal edema, and retinal edema. Retinal vein occlusion (RVO) (e.g., central (CRVO) and branch (BRVO) forms), choroidal neovascularization (CNV) (e.g., myopic CNV), corneal neovascularization, diseases associated with corneal neovascularization, retinal neovascularization, diseases associated with retinal / choroidal neovascularization, central serous retinopathy (CSR), pathological myopia, von Hippel-Lindau disease, ocular histoplasmosis, familial exudative vitreoretinopathy (FEVR), Coats' disease, Norrie's disease, osteoporosis Retinal abnormalities associated with opioid pseudoglioma syndrome (OPPG), subconjunctival hemorrhage, rubeosis, ocular neovascular disease, neovascular glaucoma, retinitis pigmentosa (RP), hypertensive retinopathy, retinal angiomatous proliferation, macular vascular ectasia, iris neovascularization, intraocular neovascularization, retinal degeneration, cystoid macular edema (CME), vasculitis, papilledema, retinitis including, but not limited to, CMV retinitis, ocular melanoma, retinoblastoma, conjunctivitis (e.g., infectious and non-infectious conjunctivitis), These eye diseases include, but are not limited to, ocular neovascularization, vascular leakage, and / or retinal edema or atrophy, including ocular ocular conditions such as glaucoma, glaucoma, and retinal atrophy.Further exemplary ocular disorders include diseases associated with retinoschisis (abnormal division of the retinal neurosensory layer), rubeosis (neovascularization of the angle), and diseases caused by abnormal proliferation of fibrovascular or fibrous tissue (including all forms of proliferative vitreoretinopathy).

[0282] Exemplary diseases associated with corneal neovascularization include, but are not limited to, epidemic keratoconjunctivitis, vitamin A deficiency, contact lens overwear, atopic keratitis, superior limbal keratitis, pterygium, keratitis sicca, Sjogren's syndrome, acne rosacea, phylectenulosis, syphilis, mycobacterial infections, fatty degeneration, chemical burns, bacterial ulcers, fungal ulcers, herpes simplex infections, herpes zoster infections, protozoal infections, Kaposi's sarcoma, Mooren's ulcer, Therrien's peripheral corneal degeneration, peripheral keratolysis, rheumatoid arthritis, generalized erythema, polyarteritis nodosa, trauma, Wegener's sarcoidosis, scleritis, Steven-Johnson syndrome, pemphigoid, radial keratotomy, and post-corneal transplant rejection.

[0283] Exemplary diseases associated with choroidal neovascularization and defects in the retinal vasculature, including increased vascular leakage, aneurysms, and capillary dropout, include, but are not limited to, diabetic retinopathy, macular degeneration, sickle cell anemia, sarcoid, syphilis, pseudoxanthoma elasticum, Paget's disease, venous occlusion, arterial occlusion, carotid occlusive disease, chronic uveitis / vitreous inflammation, mycobacterial infections, Lyme disease, systemic lupus erythematosus, retinopathy of prematurity, retinal edema (including macular edema), Eales' disease, Behcet's disease, infections causing retinitis or choroiditis (e.g., multifocal choroid), presumed ocular histoplasmosis, Best's disease (vitreomacular degeneration), myopia, optic disc, pars planitis, retinal detachment (e.g., chronic retinal detachment), hyperviscosity syndrome, toxoplasmosis, trauma, and post-laser complications.

[0284] Exemplary diseases associated with atrophy of retinal tissue (photoreceptors and the underlying RPE) include, but are not limited to, atrophic or non-exudative AMD (e.g., geographic atrophy or advanced dry AMD), macular atrophy (e.g., atrophy associated with neovascularization and / or geographic atrophy), diabetic retinopathy, Stargardt's disease, Sorsby-Fundus dystrophy, retinoschisis, and retinitis pigmentosa.

[0285] Exemplary inflammatory conditions include asthma (e.g., allergic asthma, exercise-induced asthma, aspirin-sensitive / exacerbated asthma, atopic asthma, severe asthma, mild asthma, moderate-to-severe asthma, corticosteroid-naive asthma, chronic asthma, corticosteroid-resistant asthma, corticosteroid-refractory asthma, newly diagnosed untreated asthma, smoking-induced asthma, corticosteroid-uncontrolled asthma, etc.), airway inflammation, airway hyperresponsiveness, airway hyperresponsiveness, sinusitis, sinusitis with polyps, nasal polyposis, arthritis (e.g., osteoarthritis, rheumatoid arthritis, collagenase-associated asthma, etc.), and / or inflammatory conditions, including but not limited to: inflammatory diseases, eosinophilic inflammation, mast cell-mediated inflammatory diseases, sepsis, septic shock, seronegative tenosynovitis and arthropathy (SEA) syndrome, osteoporosis, eosinophilic esophagitis, scleroderma, dermatitis, atopic dermatitis, allergic rhinitis, bullous pemphigoid, chronic urticaria, chondritis, polymyalgia rheumatica, polyarteritis nodosa, Wegener's granulomatosis, Behçet's disease, myositis, polymyolitis, dermatomyositis, vasculitis, arteritis, diabetic nephropathy, interstitial These conditions include: urinary bladder inflammation, graft-versus-host disease (GVHD), gastrointestinal inflammatory conditions (e.g., inflammatory bowel disease (IBD), ulcerative colitis (UC), Crohn's disease (CD)), colitis (e.g., colitis caused by external stimuli (e.g., resulting from or associated with therapeutic regimens such as chemotherapy, radiation therapy, etc.), infectious colitis, ischemic colitis, collagenous or lymphocytic colitis, necrotizing enterocolitis, colitis in conditions such as chronic granulomatous disease and celiac disease, food allergies, gastritis, infectious gastritis or enteritis (e.g., chronic active gastritis due to Helicobacter pylori infection), and colitis caused by infectious agents. and other forms of gastroenteritis caused by respiratory tract infections), and inflammatory lung diseases (e.g., chronic obstructive pulmonary disease (COPD), eosinophilic pulmonary inflammation, infection-induced lung diseases (including those associated with viral (e.g., influenza, parainfluenza, rotavirus, human metapneumovirus, respiratory syncytial virus), bacterial, fungal (e.g., Aspergillus), parasitic, or prion infections), allergen-induced lung diseases, pollutant-induced lung diseases (e.g., asbestosis, silicosis, or berylliosis), gastric aspiration-induced lung diseases, immune dysregulation, inflammatory conditions with a genetic predisposition such as cystic fibrosis,These include lung disease due to physical trauma (such as ventilator injury), emphysema, bronchitis, sarcoidosis, histiocytosis, lymphangioleiomyomatosis, acute lung injury, acute respiratory distress syndrome, chronic lung disease, bronchopulmonary dysplasia, pneumonia (e.g., community-acquired pneumonia, hospital-acquired pneumonia, ventilator-associated pneumonia, viral pneumonia, bacterial pneumonia, severe pneumonia), airway deterioration, and acute respiratory distress syndrome (ARDS).

[0286] Exemplary immune disorders include those mediated at least in part by mast cells, such as asthma (including allergic asthma), eczema, itch, allergies, atopic allergies, anaphylaxis, anaphylactic shock, allergic bronchopulmonary aspergillosis, allergic rhinitis, allergic conjunctivitis, as well as rheumatoid arthritis, juvenile rheumatoid arthritis, psoriatic arthritis, pancreatitis, psoriasis, plaque psoriasis, guttate psoriasis, inverse psoriasis, pustular psoriasis, erythroderma, and the like. Autoimmune disorders include psoriasis, paraneoplastic autoimmune diseases, autoimmune hepatitis, bullous pemphigoid, myasthenia gravis, inflammatory bowel disease, Crohn's disease, ulcerative colitis, celiac disease, thyroiditis (such as Graves' disease), Sjogren's syndrome, Guillain-Barré disease, Raynaud's phenomenon, Addison's disease, liver diseases (e.g., primary biliary cirrhosis, primary sclerosing cholangitis, nonalcoholic fatty liver disease, and nonalcoholic steatohepatitis), and diabetes (e.g., type 1 diabetes).

[0287] As used herein, the terms "fibrotic disorder" and "fibrosis" refer to conditions involving the formation of excess fibrous connective tissue in an organ or tissue. Exemplary fibrotic disorders include pulmonary fibrosis, liver fibrosis (e.g., fibrosis associated with cirrhosis (e.g., alcohol-induced cirrhosis, viral-induced cirrhosis, post-hepatitis C cirrhosis, liver cirrhosis, and primary biliary cirrhosis), schistosomiasis, cholangitis (e.g., sclerosing cholangitis), and autoimmune-induced hepatitis), kidney fibrosis (e.g., tubulointerstitial fibrosis, scleroderma, diabetic nephritis, and glomerulonephritis), skin fibrosis (e.g., scleroderma, hypertrophic and keloid scars, nephrogenic fibrosing dermatosis), and inflammatory bowel disease (e.g., inflammatory bowel disease). , and burns), myelofibrosis, neurofibromatosis, fibromas, intestinal fibrosis, and fibrous adhesions resulting from surgical procedures), cardiac fibrosis (e.g., fibrosis associated with myocardial infarction), vascular fibrosis (e.g., fibrosis associated with post-angioplasty arterial restenosis and atherosclerosis), ocular fibrosis (e.g., fibrosis associated with proliferative vitreoretinopathy after cataract surgery and retroorbital fibrosis), and myelofibrosis (e.g., idiopathic myelofibrosis and drug-induced myelofibrosis). Fibrosis can be organ-specific or systemic (e.g., systemic sclerosis and fibrosis associated with GVHD).

[0288] Examples of pulmonary fibrosis include, for example, lung or pulmonary fibrosis associated with idiopathic pulmonary fibrosis, fibrosis associated with collagen vascular disease, Hermansky-Pudlak syndrome, adult respiratory distress syndrome, nonspecific interstitial pneumonia, respiratory bronchiolitis, sarcoidosis, histiocytosis X, bronchiolitis obliterans, and idiopathic organizing pneumonia. In one embodiment, the pulmonary fibrosis is idiopathic pulmonary fibrosis.

[0289] As used herein, an "eosinophilic disorder" is a disease associated with excessive eosinophil numbers that may present with atypical symptoms due to the level or activity of eosinophils locally or systemically in the body. Eosinophilic disorders include, but are not limited to, asthma (including aspirin-sensitive asthma, atopic asthma, and severe asthma), eosinophilic inflammation, atopic dermatitis, allergic rhinitis (including seasonal allergic rhinitis), non-allergic rhinitis, chronic eosinophilic pneumonia, allergic bronchopulmonary aspergillosis, celiac disease, Churg-Strauss syndrome (periarteritis nodosa and atopy), eosinophilic myalgia syndrome, hypereosinophilic syndrome, edematous reactions including episodic angioedema, helminth infections (in which eosinophils may play a protective role), onchocercal dermatitis; eosinophil-associated gastrointestinal disorders (EGID), including but not limited to eosinophilic esophagitis, eosinophilic gastritis, eosinophilic gastroenteritis, eosinophilic enteritis, and eosinophilic colitis; nasal micropolyposis and polyposis, aspirin intolerance, and obstructive sleep apnea. Eosinophil-derived secretions have also been implicated in promoting angiogenesis and connective tissue formation in tumors and in the fibrotic response seen in conditions such as chronic asthma, Crohn's disease, scleroderma, and endocardial fibrosis (Munitz et al. Allergy 59:268-275, 2004; Adamko et al. Allergy 60:13-22, 2005; Oldhoff et al. Allergy 60:693-696, 2005). Other examples include cancer (e.g., glioblastoma (e.g., glioblastoma multiforme) and non-Hodgkin's lymphoma (NHL)), atopic dermatitis, allergic rhinitis, inflammatory bowel disease, fibrosis (e.g., pulmonary fibrosis (e.g., idiopathic pulmonary fibrosis (IPF) and pulmonary fibrosis secondary to sclerosis) and liver fibrosis), and COPD.

[0290] Examples of infectious diseases include helminth infections (e.g., nematode infections such as Trichuris muris infection in mice, which is a model for infection with the human parasite Trichuris trichiura), protozoan infections (e.g., Leishmania mori), and viral infections (e.g., respiratory syncytial virus infection and influenza virus infection).

[0291] Examples of pain include inflammatory pain, hyperalgesia (e.g., mechanical hyperalgesia), allodynia, and hyperalgesia (e.g., cutaneous and joint hyperalgesia, which may or may not be antigen-induced).

[0292] Examples of central nervous system diseases include subarachnoid hemorrhage, inflammatory diseases of the central nervous system, neurodegenerative diseases (e.g., Alzheimer's disease, experimental autoimmune encephalomyelitis, multiple sclerosis, Parkinson's disease, Huntington's disease), bipolar disorder, and infections of the central nervous system (such as viral infections).

[0293] Examples of solid tumors include tumors of the colon, breast, prostate, lung, kidney, liver, pancreas, ovary, head and neck, oral cavity, stomach, duodenum, small intestine, large intestine, gastrointestinal tract, anus, gallbladder, labia, nasopharynx, skin, uterus, male reproductive organs, urinary tract, bladder, and skin. Solid tumors of non-epithelial origin include sarcomas, brain tumors, and bone tumors.

[0294] The above list is not comprehensive, and one of ordinary skill in the art will understand that a disease or disorder may fall within various categories. For example, asthma may be classified in some cases as both an inflammatory and an immune disorder, and may be considered by some clinicians to be an autoimmune disorder.

[0295] "IL-33 axis binding antagonist" refers to a molecule that inhibits the interaction of an IL-33 axis binding partner with its binding partner. As used herein, IL-33 axis binding antagonists include IL-33 binding antagonists, ST2 binding antagonists, and IL1RAcP binding antagonists.Exemplary IL-33 axis binding antagonists include anti-IL-33 antibodies and antigen-binding fragments thereof (e.g., anti-IL-33 antibodies such as ANB-020 (AnaptysBio, Inc.)) or antibodies described in US10093730, EP1725261, U.S. Pat. No. 8,187,596, WO2011031600, WO2014164959, WO2015099175, or WO2015106080 (each of which is referenced herein). any of the antibodies described in WO 2014 / 152195, which is incorporated herein by reference in its entirety); polypeptides that bind to IL-33 and / or its receptors (ST2 and / or IL-1RACP) and block the ligand-receptor interaction (e.g., ST2-Fc proteins such as those described in WO 2014 / 152195, which is incorporated herein by reference in its entirety; immunoadhesins, peptibodies, and soluble ST2, or derivatives thereof). anti-IL-33 receptor antibodies (e.g., anti-ST2 antibodies, e.g., AMG-282 (Amgen) or STLM15 (Janssen), or any of the anti-ST2 antibodies described in WO 2013 / 173761 and WO 2013 / 165894 (each of which is incorporated by reference in its entirety); or ST2-Fc proteins such as those described in WO 2013 / 173761; WO 2013 / 165894; or WO 2014 / 152195 (each of which is incorporated by reference in its entirety); and IL-33 receptor antagonists, such as small molecule inhibitors, aptamers that bind to IL-33, nucleic acids that hybridize to IL-33 axis nucleic acid sequences under stringent conditions (e.g., short interfering RNA (siRNA) or clustered regularly interspaced short palindromic repeats RNA (clustered Critical RNAs include single guide RNAs (sgRNAs) with crRNA and tracrRNA sequences as described in Mali et al. (Science. 339:823-26, 2013), which are incorporated herein by reference in their entirety.

[0296] As used herein, "chemoattractant receptor-like molecule (CRTH2) expressed on Th2 cells" refers to any native CRTH2 from any vertebrate source, including mammals such as primates (e.g., humans) and rodents (e.g., mice and rats), unless otherwise specified. CRTH2 also refers to G protein-coupled receptor 44 (GPR44), cluster of differentiation 294 (CD294), DL1R, and DP2. The term encompasses "full-length," unprocessed CRTH2 and any form of CRTH2 resulting from intracellular processing. The amino acid sequence of an exemplary human CRTH2 can be found, for example, at UniProtKB Accession No. Q9Y5Y4.

[0297] The term "CRTH2 binding antagonist" refers to a molecule that reduces, blocks, inhibits, abrogates, or interferes with signal transduction resulting from the interaction of CRTH2 with one or more of its binding partners, such as prostaglandin D2. Exemplary CRTH2 binding antagonists known in the art include, for example, AMG-853, AP768, AP-761, MLN6095, and ACT129968.

[0298] The term "interleukin-5 (IL-5)," as used herein, unless otherwise specified, refers to any naturally occurring IL-5 from any vertebrate source, including mammals such as primates (e.g., humans) and rodents (e.g., mice and rats). The term encompasses "full-length," unprocessed IL-5 and any form of IL-5 resulting from intracellular processing. The term also encompasses naturally occurring variants of IL-5, such as splice variants or allelic variants. The amino acid sequence of an exemplary IL-5 can be found, for example, at UniProtKB Accession No. P05113.

[0299] The term "IL-5 binding antagonist" refers to a molecule that reduces, blocks, inhibits, abrogates, or interferes with signal transduction resulting from the interaction of IL-5 with one or more of its binding partners, such as IL-5 receptor alpha (IL5RA). Exemplary IL-5 binding antagonists that can be used in the methods of the disclosure include, for example, anti-IL-5 antibodies (e.g., mepolizumab and reslizumab) and anti-IL-5R antibodies.

[0300] As used herein, the term "interleukin-13 (IL-13)" refers to any naturally occurring IL-13 from any vertebrate source, including mammals such as primates (e.g., humans) and rodents (e.g., mice and rats), unless otherwise specified. IL-13 is a cytokine secreted by many cell types, including type 2 T helper (Th2) cells. The term encompasses "full-length," unprocessed IL-13 and any form of IL-13 resulting from intracellular processing. The amino acid sequence of an exemplary human IL-13 can be found, for example, at UniProtKB Accession No. P35225.

[0301] The term "IL-13 binding antagonist" refers to a molecule that reduces, blocks, inhibits, abrogates, or interferes with signal transduction resulting from the interaction of IL-13 with one or more of its binding partners, such as IL-4 receptor alpha (IL4Rα), IL-13 receptor alpha 1 (IL13RA1), and IL-13 receptor alpha 2 (IL13RA2). IL-13 binding antagonists include anti-IL-13 antibodies, such as lebrikizumab, 228B / C-1, 228A-4, 22726, and 22743 (see, e.g., U.S. Patent Nos. 7,674,459; 8,067,199; 8,088,618; 8,318,160; and 8,734,797).

[0302] As used herein, the term "interleukin-17 (IL-17)," unless otherwise specified, refers to any naturally occurring IL-17 from any vertebrate source, including mammals such as primates (e.g., humans) and rodents (e.g., mice and rats), and includes the family members IL-17A, IL-17B, IL-17C, IL-17D, IL-17E, and IL-17F. The term also encompasses "full-length," unprocessed IL-17 and any form of IL-17 resulting from intracellular processing. The amino acid sequence of an exemplary human IL-17A can be found, for example, at UniProtKB Accession No. Q16552. The amino acid sequence of an exemplary human IL-17B can be found, for example, at UniProtKB Accession No. Q9UHF5. The amino acid sequence of an exemplary human IL-17C can be found, for example, at UniProtKB Accession No. Q9P0M4. The amino acid sequence of an exemplary human IL-17D can be found, for example, under UniProtKB accession number Q8TAD2. The amino acid sequence of an exemplary human IL-17E can be found, for example, under UniProtKB accession number Q9H293. The amino acid sequence of an exemplary human IL-17F can be found, for example, under UniProtKB accession number Q96PD4.

[0303] The term "IL-17 binding antagonist" refers to a molecule that reduces, blocks, inhibits, abrogates, or interferes with signal transduction resulting from the interaction of IL-17 with one or more of its binding partners, such as interleukin-17 receptor (IL-17R) family member proteins interleukin-17 receptor A (IL17RA), interleukin-17 receptor B (IL17RB), interleukin-17 receptor C (IL17RC), interleukin-17 receptor D (IL17RD), interleukin-17 receptor E (IL17RE), and interleukin-17 receptor E-like (IL17REL). Exemplary IL-17 binding antagonists include, for example, anti-IL-17 antibodies (e.g., ixekizumab (LY2439821)) and anti-IL-17R antibodies (e.g., brodalumab (AMG-827)).

[0304] As used herein, the term "Janus kinase 1 (JAK1)" refers to any native JAK1 from any vertebrate source, including mammals such as primates (e.g., humans) and rodents (e.g., mice and rats), unless otherwise specified. The term encompasses "full-length," unprocessed JAK1 and any form of JAK1 resulting from processing within a cell. The term also encompasses naturally occurring variants of JAK1, such as splice variants or allelic variants. The amino acid sequence of an exemplary JAK1 can be found, for example, at UniProtKB Accession No. P23458.

[0305] The term "JAK1 antagonist," as used herein, refers to a compound or agent that inhibits or reduces the biological activity of JAK1. Exemplary JAK1 antagonists include small molecule inhibitors (e.g., ruxolitinib, GLPG0634, and GSK2586184).

[0306] The term "ST2 binding antagonist" refers to a molecule that inhibits the interaction of ST2 with IL-33, IL1RAcP, and / or a second ST2 molecule. The ST2 binding antagonist may be a protein such as an "ST2-Fc protein" comprising an IL-33 binding domain (e.g., all or part of an ST2 or IL1RAcP protein) and a multimerization domain (e.g., the Fc portion of an immunoglobulin, e.g., the Fc domain of an IgG selected from the isotypes IgG1, IgG2, IgG3, and IgG4, and any allotype within each isotype group), attached to each other directly or indirectly via a linker (e.g., a serine-glycerin (SG) linker, a glycine-glycine (GG) linker, or a variant thereof (e.g., an SGG, GGS, SGS, or GSG linker)), including, but not limited to, the ST2-Fc proteins and variants thereof described in WO 2013 / 173761, WO 2013 / 165894, and WO 2014 / 152195, each of which is incorporated herein by reference in its entirety. In some embodiments, the ST2 binding antagonist may be an anti-ST2 antibody, such as AMG-282 (Amgen) or STLM15 (Janssen), or any of the anti-ST2 antibodies described in WO 2013 / 173761 and WO 2013 / 165894.

[0307] As used herein, the term "tryptase beta" refers to any naturally occurring tryptase beta from any vertebrate source, including mammals such as primates (e.g., humans) and rodents (e.g., mice and rats), unless otherwise specified. As used herein, the term encompasses tryptase beta-1 (encoded by the TPSAB1 gene, which also encodes tryptase alpha-1) and tryptase beta-2 (encoded by the TPSB2 gene). The term encompasses "full-length," unprocessed tryptase beta, as well as any form of tryptase beta resulting from processing within cells. The amino acid sequence of an exemplary human tryptase beta-2 can be found, for example, under UniProtKB accession number P20231.

[0308] The term "tryptase-beta antagonist," as used herein, refers to a compound or agent that inhibits or reduces the biological activity of tryptase-beta.

[0309] As used herein, the term "Factor D," unless otherwise specified, refers to any native Factor D from any vertebrate source, including mammals such as primates (e.g., humans) and rodents (e.g., mice and rats). Factor D is also known as C3 proactivator convertase, properdin Factor D esterase, Factor D (complement), complement Factor D, CFD, and adipsin. The term encompasses "full-length," unprocessed Factor D and any form of Factor D resulting from processing within a cell. The amino acid sequence of an exemplary human Factor D can be found, for example, under UniProtKB Accession No. P00746.

[0310] The term "Factor D binding antagonist," as used herein, refers to a compound or agent that inhibits or reduces the biological activity of Factor D. Exemplary Factor D binding antagonists include, for example, small molecule inhibitors and anti-Factor D antibodies, such as any of the anti-Factor D antibodies described in WO 2007 / 056227, WO 01 / 70818, and / or U.S. Patent Application Publication No. 2002 / 0081293, each of which is incorporated by reference in its entirety. In some embodiments, the anti-Factor D antibody is or is derived from monoclonal antibody 166-32, produced by the hybridoma deposited with the ATCC and designated HB12476.

[0311] As used herein, "High-temperature requirement A serine peptidase 1" or "HtrA1" refers to any naturally occurring HtrA1 from any vertebrate source, including mammals such as primates (e.g., humans) and rodents (e.g., mice and rats), unless otherwise specified. HtrA1 is also known in the art as HtrA serine peptidase 1, L56, and serine protease 11. The term encompasses "full-length," unprocessed HtrA1 and any form of HtrA1 resulting from intracellular processing. The term also encompasses naturally occurring variants of HtrA1, such as splice variants or allelic variants. The amino acid sequence of an exemplary human HtrA1 can be found, for example, under UniProtKB accession number Q92743.

[0312] The term "HtrA1 binding antagonist," as used herein, refers to a compound or agent that inhibits or reduces the biological activity of HtrA1. Exemplary HtrA1 binding antagonists include, for example, small molecule inhibitors and anti-HtrA1 antibodies, such as any of the anti-HtrA1 antibodies described in U.S. Pat. No. 1,042,1822 or U.S. Pat. No. 9,738,727 (each of which is incorporated herein by reference in its entirety).

[0313] The term "vascular endothelial growth factor" or "VEGF" refers to vascular endothelial growth factor protein A, as exemplified by Swiss Prot Accession Number P15692. The term "VEGF" encompasses proteins having the amino acid sequence of Swiss Prot Accession Number P15692, as well as homologs and isoforms thereof. The term "VEGF" also refers to known isoforms of VEGF, e.g., splice isoforms, e.g., VEGF 111 , VEGF 121 , VEGF 145 , VEGF 165 , VEGF 189 , and VEGF 206 , and their naturally occurring alleles and processed forms (VEGF 165 These include VEGFs derived from non-human species such as mouse, rat, or primate. VEGFs derived from specific species may be designated by terms such as hVEGF for human VEGF and mVEGF for mouse VEGF. The term "VEGF" is also used to refer to truncated forms of the polypeptide, including amino acids 8-109 or 1-109 of the 165-amino acid human vascular endothelial growth factor. Reference to any such form of VEGF is referred to in this application as, for example, "VEGF." 109 ", "VEGF(8-109)", "VEGF(1-109)", or "VEGF 165". The amino acid positions of "truncated" native VEGF are numbered as they appear in the native VEGF sequence. For example, amino acid position 17 (methionine) in truncated native VEGF is also position 17 (methionine) in native VEGF. Truncated native VEGF has binding affinity for the KDR and Flt-1 receptors comparable to native VEGF. The term "VEGF variant," as used herein, refers to a VEGF polypeptide that contains one or more amino acid mutations in the native VEGF sequence. In some cases, the one or more amino acid mutations include amino acid substitution(s). For purposes of concisely designating the VEGF variants described herein, it should be noted that the numbers refer to the amino acid residue position along the amino acid sequence of the putative native VEGF (provided in Leung et al., supra, and Houck et al., supra). Unless otherwise specified, the term "VEGF," as used herein, refers to VEGF-A.

[0314] The term "VEGF antagonist," as used herein, refers to a molecule capable of binding to VEGF, reducing VEGF expression levels, or neutralizing, blocking, inhibiting, abrogating, reducing, or interfering with the biological activities of VEGF, including, but not limited to, VEGF binding to one or more VEGF receptors, VEGF signal transduction, and VEGF-mediated angiogenesis and endothelial cell survival or proliferation. For example, a molecule capable of neutralizing, blocking, inhibiting, abrogating, reducing, or interfering with the biological activities of VEGF may exert its effect by binding to one or more VEGF receptors (VEGFRs) (e.g., VEGFR1, VEGFR2, VEGFR3, membrane-bound VEGF receptors (mbVEGFRs), or soluble VEGF receptors (sVEGFRs)). VEGF antagonists useful in the methods of the present disclosure include polypeptides that specifically bind to VEGF, anti-VEGF antibodies and antigen-binding fragments thereof, receptor molecules and derivatives that specifically bind to VEGF and thereby block binding to one or more receptors, fusion proteins (e.g., VEGF-Trap (Regeneron)), and VEGF 121-Gelonin (Peregrine). VEGF antagonists also include antagonist variants of VEGF polypeptides, antisense nucleobase oligomers complementary to at least a fragment of a nucleic acid molecule encoding a VEGF polypeptide, small RNAs complementary to at least a fragment of a nucleic acid molecule encoding a VEGF polypeptide; ribozymes targeting VEGF; peptibodies against VEGF; and VEGF aptamers. VEGF antagonists also include polypeptides that bind to VEGFR, anti-VEGFR antibodies and antigen-binding fragments thereof, as well as derivatives or fusion proteins that bind to VEGFR and thereby block, inhibit, abrogate, reduce, or interfere with the biological activity of VEGF (e.g., VEGF signal transduction). VEGF antagonists also include non-peptide small molecules that can bind to VEGF or VEGFR and block, inhibit, abrogate, reduce, or interfere with the biological activity of VEGF. Thus, the term "VEGF activity" specifically includes VEGF-mediated biological activity of VEGF. In certain embodiments, the VEGF antagonist reduces or inhibits the expression level or biological activity of VEGF by at least 10%, 20%, 30%, 40%, 50%, 60%, 70%, 80%, 90% or more. In some embodiments, the VEGF inhibited by the VEGF-specific antagonist is VEGF(8-109), VEGF(1-109), or VEGF 165 is.

[0315] As used herein, VEGF antagonists include anti-VEGFR2 antibodies and related molecules (e.g., ramucirumab, tanibirumab, aflibercept), anti-VEGFR1 antibodies and related molecules (e.g., icrucumab, aflibercept (VEGF Trap-Eye, EYLEA®), and ziv-aflibercept (VEGF Trap, ZALTRAP®)), bispecific VEGF antibodies (e.g., MP-0250, vanucizumab (VEGF-ANG2), and the bispecific antibodies disclosed in U.S. Patent Application Publication No. 2001 / 0236388), bispecific antibodies comprising a combination of two of anti-VEGF, anti-VEGFR1, and anti-VEGFR2 arms, anti-VEGF antibodies (e.g., bevacizumab, sevacizumab), mab, and ranibizumab), and non-peptide small molecule VEGF antagonists (e.g., pazopanib, axitinib, vandetanib, stivarga, cabozantinib, lenvatinib, nintedanib, orantinib, telatinib, dovitinib, cediranib, motesanib, surufatinib, apatinib, foretinib, famitinib, and tivozanib).

[0316] The terms "anti-VEGF antibody," "antibody that binds VEGF," and "antibody that specifically binds VEGF" refer to an antibody that can bind VEGF with sufficient affinity such that the antibody is useful as a diagnostic and / or therapeutic agent in targeting VEGF. In one embodiment, the extent of binding of an anti-VEGF antibody to an unrelated, non-VEGF protein is less than about 10% of the binding of the antibody to VEGF, as measured, for example, by radioimmunoassay (RIA). In certain embodiments, an antibody that binds VEGF has an affinity of ≦1 μM, ≦100 nM, ≦10 nM, ≦1 nM, ≦0.1 nM, ≦0.01 nM, or ≦0.001 nM (e.g., 10 -8 M or less, e.g. 10 -8 ~10 -13 M, e.g. 10 -9 M~10 -13 In certain embodiments, the anti-VEGF antibody binds to an epitope of VEGF that is conserved among VEGFs from different species.

[0317] In certain embodiments, anti-VEGF antibodies can be used as therapeutic agents in targeting and interfering with diseases or conditions involving VEGF activity. Antibodies can also be subjected to other biological activity assays, e.g., to assess their effectiveness as therapeutic agents. Such assays are known in the art and depend on the antibody's target antigen and intended use. Examples include HUVEC inhibition assays; tumor cell growth inhibition assays (e.g., those described in WO 89 / 06692); antibody-dependent cellular cytotoxicity (ADCC) and complement-mediated cytotoxicity (CDC) assays (U.S. Pat. No. 5,500,362); and agonist activity or hematopoietic assays (see WO 95 / 27062). Anti-VEGF antibodies typically do not bind to other VEGF homologs, such as VEGF-B or VEGF-C, or other growth factors, such as PIGF, PDGF, or bFGF. In one embodiment, the anti-VEGF antibody is a monoclonal antibody that binds to the same epitope as monoclonal anti-VEGF antibody A4.6.1, produced by hybridoma ATCC HB10709. In another embodiment, the anti-VEGF antibody is a recombinant humanized anti-VEGF monoclonal antibody produced according to Presta et al. (1997) Cancer Res. 57:4593-4599, including, but not limited to, the antibody known as bevacizumab (BV; AVASTIN®).

[0318] The anti-VEGF antibody "bevacizumab (BV)," also known as "rhuMAb VEGF" or "AVASTIN®," is a recombinant humanized anti-VEGF monoclonal antibody generated according to Presta et al. (1997) Cancer Res. 57:4593-4599. It contains mutated human IgG1 framework regions and antigen-binding complementarity-determining regions derived from the murine anti-hVEGF monoclonal antibody A.4.6.1, which blocks binding of human VEGF to its receptor. Approximately 93% of the amino acid sequence of bevacizumab, including most of the framework regions, is derived from human IgG1, and approximately 7% of the sequence is derived from the murine antibody A4.6.1. Bevacizumab has a molecular weight of approximately 149,000 daltons and is glycosylated. Bevacizumab and other humanized anti-VEGF antibodies are further described in U.S. Patent No. 6,884,879, issued February 26, 2005, the entire disclosure of which is expressly incorporated herein by reference. Additional preferred antibodies include the G6 or B20 series antibodies (e.g., G6-31, B20-4.1) described in PCT Application Publication Nos. WO 2005 / 012359 and WO 2005 / 044853, which are incorporated herein by reference in their entireties. For additional preferred antibodies, see U.S. Patent Nos. 7,060,269, 6,582,959, 6,703,020, 6,054,297, WO 98 / 45332, WO 96 / 30046, WO 94 / 10202, EP 0666868 B1, U.S. Patent Application Publication Nos. 2006009360, 20050186208, 20030206899, 20030190317, 20030203409, and 20050112126, and Popkov et al., Journal of Immunological Methods 288:149-164 (2004). Other preferred antibodies include antibodies that bind to a functional epitope on human VEGF that includes residues F17, M18, D19, Y21, Y25, Q89, 191, K101, E103, and C104, or that includes residues F17, Y21, Q22, Y25, D63, 183, and Q89.Additional anti-VEGF antibodies include those described in PCT Application Publication No. WO 2009 / 155724.

[0319] The anti-VEGF antibody "ranibizumab," also known as "LUCENTIS®" or "rhuFab V2," is a humanized, affinity-matured anti-human VEGF Fab fragment. Ranibizumab is produced by standard recombinant technology methods in E. coli expression vectors and bacterial fermentation. Ranibizumab is non-glycosylated and has a molecular weight of approximately 48,000 daltons. See WO 98 / 45331 and U.S. Patent Application Publication No. 2003 / 0190317.

[0320] Chemotherapeutic agents are chemical compounds useful in the treatment of cancer. Examples of chemotherapeutic agents include alkylating agents such as thiotepa and cyclosphosphamide (CYTOXAN®); alkylsulfonates such as busulfan, improsulfan, and piposulfan; aziridines such as benzodopa, carboquone, mesuredopa, and uredopa; ethylenimines and methylamelamines, including altretamine, triethylenemelamine, triethylenephosphoramide, triethylenethiophosphoramide, and trimethylmelamine; acetogens such as acetaminophen, ... camptothecin (especially bullatacin and bullatacinone); delta-9-tetrahydrocannabinol (dronabinol, MARINOL®); beta-lapachone; lapachol; colchicine; betulinic acid; camptothecin (synthetic analogs topotecan (HYCAMTIN®), CPT-11 (irinotecan, CAMPTOSAR®), acetylcamptothecin, scopolectin, and 9-aminocamptothecin); bryostatin; kallistatin; CC-1065 ( including its synthetic analogs adozelesin, carzelesin, and bizelesin; podophyllotoxin; podophyllic acid; teniposide; teniposide; cryptophycins (especially cryptophycin 1 and cryptophycin 8); dolastatins; duocarmycins (synthetic analogs, such as KW-2189 and CB1-TM1); eluterobin; pancratistatin; sarcodictyin; spongistatin; chlorambucil, chlornaphazine, chlorophosphamide, estramustine, nitrogen mustards such as ifosfamide, mechlorethamine, mechlorethamine oxide hydrochloride, melphalan, nobembine, fenesterine, prednimustine, trofosfamide, and uracil mustard; nitrosoureas such as carmustine, chlorozotocin, fotemustine, lomustine, nimustine, and ranimustine; antibiotics such as enediyne antibiotics (e.g., calicheamicin, particularly calicheamicin γ1I and calicheamicin ω1I (see, e.g., Nicolaou et al., Angew. Chem Intl. Ed. Engl., 33:183-186 (1994))); CDP323, an oral alpha-4 integrin inhibitor; dynemicins, including dynemicin A;Esperamicin, plus neocarzinostatin chromophore and related enediyne antibiotic chromophores), aclacinomycin, actinomycin, anthramycin, azaserine, bleomycin, cactinomycin, carabicin, caminomycin, carzinophilin, chromomycin, dactinomycin, daunorubicin, detorubicin, 6-diazo-5-oxo-L-norleucine, doxorubicin (ADRIAMYCIN®, morpholino-doxorubicin, cyanomorpholino-doxorubicin, 2-pyrrolino-doxorubicin, doxorubicin hydrochloride liposome injection (DOXIL®), liposomal doxorubicin TLC D-99 (including MYOCET®), pegylated liposomal doxorubicin (CAELYX®, and deoxydoxorubicin), mitomycins such as epirubicin, esorubicin, idarubicin, marcelomycin, and mitomycin C, mycophenolic acid, nogalamycin, olivomycin, peplomycin, porfiromycin, puromycin, chelamycin, rodorubicin, streptonigrin, streptozocin, tubercidin, ubenimex, zinostatin, and zorubicin; antimetabolites such as methotrexate, gemcitabine (GEMZAR®), tegafur (UFTORAL®), capecitabine (XELODA®), epothilones, and 5-fluorouracil (5-FU); combretastatins; and denopterin. , folic acid analogues such as methotrexate, pteropterin, trimetrexate; purine analogues such as fludarabine, 6-mercaptopurine, thiamiprine, thioguanine; pyrimidine analogues such as ancitabine, azacitidine, 6-azauridine, carmofur, cytarabine, dideoxyuridine, doxifluridine, enocitabine, floxuridine; androgens such as calucelone, dromostanolone propionate, epitiostanol, mepitiostane, testolactone; antiadrenal agents such as aminoglutethimide, mitotein, trilostane; folic acid supplements such as furoic acid; aceglatone; aldophosphamide glycoside; aminolevulinic acid; eniluracil; amsacrine; bestravcil; bisantrene; edatraxate; defofamine; demecolcine; diaziquone;Elformitin; elliptinium acetate; epothilone; etoglucide; gallium nitrate; hydroxyurea; lentinan; lonidynin; maytansinoids such as maytansine and ansamitocin; mitoguazone; mitoxantrone; mopidanmol; nitraelin; pentostatin; phenamet; pirarubicin; losoxantrone; 2-ethylhydrazide; procarbazine; PSK® polysaccharide complex (JHS Natural Products); razoxane; rhizoxin; schizofuran; spirogermanium; tenuazonic acid; triaziquone; 2,2',2'-trichlorotriethylamine; trichothecenes (especially T-2 toxin, veraculin A, roridin A, and anguidine); urethanes; vindesine (ELDISINE®, FILDESIN®); dacarbazine; mannomustine; mitobronitol; mitolactol; pipobroman; gacytosine; arabinoside ("Ara-C"); thiotepa; taxoids, such as paclitaxel (TAXOL®), albumin-modified nanoparticle formulations of paclitaxel (ABRAXANE™), and docetaxel (TAXOTERE®); lorambucil; 6-thioguanine; mercaptopurine; methotrexate; platinum agents such as cisplatin, oxaliplatin (e.g., ELOXATIN®), and carboplatin; vincas that protect tubulin polymerization from microtubule formation (including vinblastine (VELBAN®), vincristine (ONCOVIN®), vindesine (ELDISINE®, FILDESIN®), and vinorelbine (NAVELBINE®)); etoposide (VP-16); ifosfamide; mitoxantrone; leucovorin; novantrone; edatrexate; daunomycin; aminopterin; ibandronate; the topoisomerase inhibitor RFS 2000; difluoromethylornithine (DMFO); retinoids such as retinoic acid (including bexarotene (TARGRETIN®));Bisphosphonates such as clodronate (e.g., BONEFOS® or OSTAC®), etidronate (DIDROCAL®), NE-58095, zoledronic acid / zoledronate (ZOMETA®), alendronate (FOSAMAX®), pamidronate (AREDIA®), tiludronate (SKELID®), or risedronate (ACTONEL®); troxacitabine (a 1,3-dioxolane nucleoside cytosine analog); antisense oligonucleotides, particularly those that inhibit gene expression in signaling pathways implicated in ectopic cell proliferation, such as PKC-α, Raf, H-Ras, and epidermal growth factor receptor (EGFR) (e.g., erlotinib (TARCEVA®); TM )); and VEGF-A, which reduces cell proliferation; THERATOPE® vaccines, and gene therapy vaccines, such as ALLOVECTIN® vaccine, LEUVECTIN® vaccine, and VAXID® vaccine; topoisomerase 1 inhibitors (e.g., LURTOTECAN®); rmRH (e.g., ABARELIX®); BAY439006 (sorafenib; Bayer); SU-11248 (sunitinib, SUTENT®, Pfizer); Peripheral Neoplasia (Petroleum Inhibitor); fosine, COX-2 inhibitors (e.g., celecoxib or etoricoxib), proteosome inhibitors (e.g., PS341); bortezomib (VELCADE®); CCI-779; tipifarnib (R11577); orafenib, ABT510; Bcl-2 inhibitors such as oblimersen sodium (GENASENSE®); pixantrone; EGFR inhibitors; tyrosine kinase inhibitors; serine-threonine kinase inhibitors such as rapamycin (sirolimus, RAPAMUNE®); lonafarnib (SCH 6636, SARASAR TMand pharmaceutically acceptable salts, acids, or derivatives of any of the foregoing; and CHOP (an abbreviation for the combination therapy of cyclophosphamide, doxorubicin, vincristine, and prednisolone), and FOLFOX (oxaliplatin in combination with 5-FU and leucovorin (ELOXATIN)). TM ), and pharmaceutically acceptable salts, acids, or derivatives of any of the above; and combinations of two or more of the above.

[0321] Chemotherapeutic agents, as defined herein, include "antihormonal agents" or "endocrine therapeutic agents" that act to regulate, reduce, block, or inhibit the action of hormones that can promote cancer growth.They may themselves be hormones, or may be antiestrogens with mixed agonist / antagonist profiles, including selective estrogen receptor modulators (SERMs) such as tamoxifen (NOLVADEX®), 4-hydroxytamoxifen, toremifene (FARESTON®), idoxifene, droloxifene, raloxifene (EVISTA®), trioxifene, ketoxifene, and SERM3; pure antiestrogens without agonist properties, such as fulvestrant (FASLODEX®) and EM800 (such agents may block estrogen receptor (ER) dimerization, inhibit DNA binding, increase ER turnover, and / or suppress ER levels); steroidal aromatase inhibitors such as formestane and exemestane (AROMASIN®). aromatase inhibitors, including nonsteroidal aromatase inhibitors such as anastrazole (ARIMIDEX®), letrozole (FEMARA®), and aminoglutethimide, and other aromatase inhibitors including vorozole (RIVISOR®), megestrol acetate (MEGASE®), fadrozole, and 4(5)-imidazole; luteinizing hormone-releasing hormone agonists, including leuprolide (LUPRON® and ELIGARD®), goserelin, buserelin, and tripterelin; progestins such as megestrol acetate and medroxyprogesterone acetate, estrogens such as diethylstilbestrol and Premarin, and fluoxymesterone, all-trans retinoic acid anti-androgens such as flutamide, nilutamide, and bicalutamide; and pharmaceutically acceptable salts, acids, or derivatives of any of the foregoing; and combinations of two or more of the foregoing.

[0322] The term "cytotoxic agent," as used herein, refers to a substance that inhibits or prevents the function of cells and / or causes cell death or destruction. Cytotoxic agents include radioisotopes (e.g., At 211 , I 131 , I 125 , Y 90 ,Re 186 ,Re 188 , Sm 153 , Bi 212 , P 32 , Pb 212 , and radioactive isotopes of Lu); chemotherapeutic agents or drugs (e.g., methotrexate, adriamycin, vinca alkaloids (vincristine, vinblastine, etoposide), doxorubicin, melphalan, mitomycin C, chlorambucil, daunorubicin or other intercalating agents); growth inhibitory agents; enzymes and fragments thereof, e.g., nucleases; antibiotics; toxins, such as small molecule toxins or enzymatically active toxins of bacterial, fungal, plant or animal origin (including fragments and / or variants thereof); and various anti-tumor or anti-cancer agents disclosed herein.

[0323] As used herein, a "growth inhibitor" refers to a compound or composition that inhibits cell growth either in vitro or in vivo. Thus, a growth inhibitor may significantly reduce the proportion of cells in S phase. Examples of growth inhibitors include agents that block cell cycle progression (outside of S phase), such as agents that induce G1 arrest and M-phase arrest. Classical M-phase blockers include vincas (e.g., vincristine and vinblastine), taxanes, and topoisomerase II inhibitors, such as doxorubicin, epirubicin, daunorubicin, etoposide, and bleomycin. Agents that arrest G1 also induce S-phase arrest, such as tamoxifen, prednisone, dacarbazine, mechlorestamine, cisplatin, methotrexate, 5-fluorouracil, and DNA alkylating agents such as araC. Further information can be found, for example, on page 13, in Mendelsohn et al. eds., The Molecular Basis of Cancer, Chapter 1, entitled "Cell cycle regulation, oncogenes, and antitineoplastic drugs" by Murakami et al. (WB Saunders, Philadelphia, 1995). Taxanes (paclitaxel and docetaxel) are anticancer drugs, both derived from the yew tree. Docetaxel (TAXOTERE®), derived from the European yew, is a semisynthetic analog of paclitaxel (TAXOL®). Paclitaxel and docetaxel promote the assembly of microtubules from tubulin dimers, stabilize microtubules by preventing depolymerization, and inhibit mitosis in cells.

[0324] An "isolated nucleic acid" refers to a nucleic acid molecule that has been separated from a component of its natural environment. Isolated nucleic acid includes a nucleic acid molecule contained within cells that normally contain the nucleic acid molecule, but where the nucleic acid molecule is present extrachromosomally or at a chromosomal location that is different from its natural chromosomal location.

[0325] The term "regulatory sequence" refers to DNA sequences necessary for the expression of an operably linked coding sequence in a particular host organism. Regulatory sequences that are suitable for prokaryotes include, for example, a promoter, optionally an operator sequence, and a ribosome binding site. Eukaryotic cells are known to utilize promoters, polyadenylation signals, and enhancers.

[0326] The terms "host cell," "host cell line," and "host cell culture" are used interchangeably and refer to cells into which exogenous nucleic acid has been introduced, including the progeny of such cells. Host cells include "transformants" and "transformed cells," which include the primary transformed cell and its progeny, regardless of the number of passages. The progeny may not be completely identical in nucleic acid content to the parent cell, but may contain mutations. Mutant progeny that have the same function or biological activity as screened or selected for in the originally transformed cell are included in the present invention. A host cell may be an "isolated host cell," which refers to a host cell that has been separated from a component of its natural environment.

[0327] A nucleic acid is "operably linked" when it is placed into a functional relationship with another nucleic acid sequence. For example, a presequence or secretory leader DNA is operably linked to DNA for a polypeptide if it is expressed as a preprotein that participates in the secretion of the polypeptide; a promoter or enhancer is operably linked to a coding sequence if it affects the transcription of the sequence; or a ribosome binding site is operably linked to a coding sequence if it is positioned so as to facilitate translation. Generally, "operably linked" means that the DNA sequences being linked are contiguous, and, in the case of a secretory leader, contiguous and in reading phase. However, enhancers need not be contiguous. Linking is accomplished by ligation at convenient restriction enzyme sites. If such sites do not exist, synthetic oligonucleotide adaptors or linkers are used in accordance with conventional practice.

[0328] "Percent (%) amino acid sequence identity" with respect to a polypeptide sequence identified herein is defined as the percentage of amino acid residues in a candidate sequence that are identical to amino acid residues in a compared polypeptide, after aligning the sequences and introducing gaps, if necessary, to achieve the maximum percent sequence identity, not counting any conservative substitutions as part of the sequence identity. Alignment for purposes of determining percent amino acid sequence identity can be achieved in a variety of ways within the skill of the art, for example, using publicly available computer software such as BLAST, BLAST-2, ALIGN, or Megalign (DNASTAR) software. Those skilled in the art can determine appropriate parameters for measuring alignment, including any algorithms necessary to achieve maximal alignment over the full length of the sequences being compared. However, for purposes herein, percent amino acid sequence identity values ​​are generated using the sequence comparison computer program ALIGN-2. The ALIGN-2 sequence comparison computer program was created by Genentech, Inc., and the source code, along with user documentation, has been filed with the U.S. Copyright Office, Washington, DC 20559, and is hereby registered under U.S. Copyright Registration No. TXU510087. The ALIGN-2 program is publicly available through Genentech, Inc., South San Francisco, California. The ALIGN-2 program should be adapted for use on a UNIX operating system, preferably Digital UNIX V4.0D. All sequence comparison parameters are set by the ALIGN-2 program and do not vary.

[0329] In situations where ALIGN-2 is used for amino acid sequence comparison, the % amino acid sequence identity of a given amino acid sequence A to, with, or relative to a given amino acid sequence B (alternatively, it may be written as a given amino acid sequence A having or comprising a certain % amino acid sequence identity to, with, or relative to a given amino acid sequence B) is calculated as follows: 100 x fraction X / Y where X is the number of amino acid residues scored as identical by the sequence alignment program ALIGN-2 in that program's alignment of A and B, and Y is the total number of amino acid residues in B. It will be understood that if the length of amino acid sequence A differs from the length of amino acid sequence B, the % amino acid sequence identity of A to B will differ from the % amino acid sequence identity of B to A. Unless otherwise specified, all % amino acid sequence identity values ​​used herein are obtained as described in the immediately preceding paragraph using the ALIGN-2 computer program.

[0330] The amino acid sequences described herein are contiguous amino acid sequences unless otherwise specified.

[0331] The term "package insert" is used to refer to instructions typically included in commercial packaging for a therapeutic product, and includes information regarding the indications, uses, dosage, administration, concomitant therapy, contraindications and / or warnings regarding such therapeutic product.

[0332] The term "pharmaceutical composition" refers to a formulation in a form that allows for the biological activity of the active ingredient contained therein to be effective and that does not contain additional components that are unacceptably toxic to the subject to which the formulation is administered.

[0333] "Pharmaceutically acceptable carrier" refers to an ingredient in a pharmaceutical formulation other than the active ingredient that is non-toxic to a subject. Pharmaceutically acceptable carriers include, but are not limited to, buffers, additives, stabilizers, or preservatives.

[0334] The term "prodrug" as used herein refers to a precursor or derivative form of a pharmaceutically active substance that has reduced cytotoxicity to tumor cells compared to the parent drug and can be enzymatically activated or converted into a more active parent form. See, for example, Wilman, "Prodrugs in Cancer Chemotherapy," Biochemical Society Transactions, 14, pp. 375-382, 615th Meeting Belfast (1986) and Stella et al., "Prodrugs: A Chemical Approach to Targeted Drug Delivery," Directed Drug Delivery, Borchardt et al. (ed.), pp. 247-267, Humana Press (1985). Prodrugs of the present invention include, but are not limited to, phosphate-containing prodrugs, thiophosphate-containing prodrugs, sulfate-containing prodrugs, peptide-containing prodrugs, D-amino acid modified prodrugs, glycosylated prodrugs, β-lactam-containing prodrugs, optionally substituted phenoxyacetamide-containing prodrugs or optionally substituted phenylacetamide-containing prodrugs, 5-fluorocytosine and other 5-fluorouridine prodrugs, which can be converted to more active cytotoxic free drugs. Examples of cytotoxic drugs that can be derivatized into prodrug forms for use in the present invention include, but are not limited to, the chemotherapeutic agents described above.

[0335] By "reducing or inhibiting" is meant the ability to cause an overall decrease, preferably of 20% or more, more preferably 50% or more, and most preferably 75%, 85%, 90%, 95% or more. Reducing or inhibiting may refer to the symptoms of the disorder being treated, the presence or size of metastases, and / or the size of the primary tumor.

[0336] A "subject" is a vertebrate, preferably a mammal, more preferably a human. Mammals include, but are not limited to, farm animals (e.g., cows and sheep), sport animals, pets (e.g., cats, dogs, and horses), primates (e.g., humans and non-human primates such as monkeys), and rodents (e.g., mice and rats).

[0337] The term "therapeutically effective amount" refers to an amount of a compound (e.g., an anti-IL-33 antibody (including an antibody fragment such as a Fab fragment) provided herein or a nucleic acid encoding an anti-IL-33 antibody provided herein) or composition (e.g., a pharmaceutical composition, e.g., a pharmaceutical composition comprising an anti-IL-33 antibody provided herein) to treat a disease or disorder of a subject. In the case of an IL-33-mediated disorder, a therapeutically effective amount of an antibody or antibody fragment (e.g., an anti-IL-33 antibody, including a bispecific anti-IL-33 antibody that binds to IL-33 and a second biological molecule, e.g., IL-13, e.g., a bispecific anti-IL-33 / anti-IL-13 antibody) may ameliorate or treat the disease, or prevent, alleviate, ameliorate, or treat symptoms associated with the disease. In the case of a proliferative disorder (e.g., a solid tumor), a therapeutically effective amount of an antibody or antibody fragment may reduce the number of cells, reduce primary tumor size, inhibit (i.e., slow to some extent, and preferably stop) cancer cell invasion into peripheral organs, inhibit (i.e., slow to some extent, and preferably stop) tumor metastasis, inhibit tumor growth to some extent, and / or alleviate to some extent one or more symptoms associated with the disorder. To the extent the antibody or antibody fragment can prevent the growth of and / or kill existing cancer cells, the antibody or antibody fragment may be cytostatic and / or cytotoxic. With respect to cancer therapy, in vivo efficacy can be measured, for example, by assessing survival time, time to disease progression (TTP), disease-free survival (DFS), progression-free survival (PFS), response rate (RR), duration of response, and / or quality of life.

[0338] As used herein, "treatment" (and grammatical variations thereof, such as "treat" or "treating") refers to a clinical intervention that attempts to alter the natural history of the individual being treated, and can be performed prophylactically or during the course of clinical pathology. Desired effects of treatment include, but are not limited to, preventing the onset or recurrence of the disease, alleviating symptoms, attenuating any direct or indirect pathological consequences of the disease, preventing metastasis, slowing the rate of disease progression, remission or alleviation of disease symptoms, and recovery or improved prognosis. In some embodiments, the antibodies disclosed herein are used to delay the onset of the disease or slow the progression of the disease. For example, a patient may be successfully "treated" for asthma if, after receiving asthma treatment, the patient shows an observable and / or measurable reduction in, or absence of, one or more of the following: recurrent wheezing, coughing, shortness of breath, chest tightness, symptoms that occur or worsen at night, symptoms caused by cold air, exercise, or exposure to allergens.

[0339] "Tumor," as used herein, refers to all neoplastic cell growth and proliferation, whether malignant or benign, and all pre-cancerous and cancerous cells and tissues.

[0340] The term "vector," as used herein, is intended to refer to a nucleic acid molecule capable of transporting another nucleic acid to which it has been linked. One type of vector is a "plasmid," which refers to a circular double-stranded DNA loop into which additional DNA segments may be ligated. Another type of vector is a phage vector. Another type of vector is a viral vector, into which additional DNA segments may be ligated. Certain vectors are capable of autonomous replication in a host cell into which they are introduced (e.g., bacterial vectors having a bacterial origin of replication and episomal mammalian vectors). Other vectors (e.g., non-episomal mammalian vectors) can be integrated into the genome of a host cell upon introduction into the host cell, and thereby are replicated along with the host genome. Moreover, certain vectors are capable of directing the expression of genes to which they are operatively linked. Such vectors are referred to herein as "recombinant expression vectors" (or simply "recombinant vectors" or "expression vectors"). In general, expression vectors utilized in recombinant DNA techniques are often in the form of plasmids. As used herein, "plasmid" and "vector" may be used interchangeably.

[0341] As used herein, the term "turbidity" refers to the cloudiness or haze of a liquid due to suspended insoluble particles. Turbidity can be assessed by measuring the optical density (OD) of a liquid sample, for example, using a spectrophotometer.

[0342] As used herein, the term "viscosity" refers to a measure of a fluid's resistance to deformation at a given rate. The SI unit of dynamic viscosity is the pascal-second (Pa s), but it is also commonly expressed as centipoise (cP), which is equivalent to 1 millipascal-second (mPa s).

[0343] II. Compositions and Methods In one aspect, the present invention is based, at least in part, on improved antibodies that bind to IL-33. The antibodies provided herein have unexpectedly advantageous properties compared to existing anti-IL-33 antibodies, including increased stability (including under conditions of chemical and photo-stress) and reduced oxidation. For example, the antibodies disclosed herein may lack tryptophan residues in CDR-H3, which may result in decreased stability due to oxidation. Furthermore, the antibodies provided herein also bind to human and cynomolgus monkey (cyno) IL-33 with high affinity and inhibitory activity, as assessed, for example, using surface plasmon resonance (SPR) and cell-based blocking assays (e.g., using HEK-BLUE™ cells), respectively. Furthermore, the antibodies provided herein have low viscosity and high solubility at high protein concentrations. The antibodies disclosed herein are useful, for example, for the treatment of IL-33-mediated disorders. The unexpectedly advantageous properties described above (including improved stability due to reduced oxidation, high solubility, and the ability to be formulated to high concentrations with low viscosity) are particularly advantageous in the context of ocular administration for the treatment of ocular disorders, such as AMD (e.g., GA). For example, without wishing to be bound by any theory, in the context of GA, targeted inhibition of IL-33 signaling in the eye may protect photoreceptors and RPE in areas adjacent to GA lesions, for example, by limiting the influx of inflammatory mononuclear phagocytes.

[0344] A. Exemplary Anti-IL-33 Antibodies In one example, provided herein is a CDR-H1 comprising the amino acid sequence of NYWMT (SEQ ID NO: 1); (b) a CDR-H2 comprising the amino acid sequence of SITYTGGGTYYPDSVKG (SEQ ID NO: 2); (c) a CDR-H3 comprising the amino acid sequence of ANYYYNTYGGFPY (SEQ ID NO: 3); (d) a CDR-L1 comprising the amino acid sequence of LASEGFSNDLA (SEQ ID NO: 4); (e) a CDR-L2 comprising the amino acid sequence of AASRLQD (SEQ ID NO: 5); and (f) a CDR-L3 comprising the amino acid sequence of QQGSKYPLT (SEQ ID NO: 6). and CDR-L3 comprising the sequence: For example, in some cases, the anti-IL-33 antibody comprises at least one, two, three, four, five, or six CDRs selected from: (a) a CDR-H1 comprising the amino acid sequence of NYWMT (SEQ ID NO: 1); (b) a CDR-H2 comprising the amino acid sequence of SITYTGGGTYYPDSVKG (SEQ ID NO: 2); (c) a CDR-H3 comprising the amino acid sequence of ANYYYNTYGGFPY (SEQ ID NO: 3); (d) a CDR-L1 comprising the amino acid sequence of LASEGFSNDLA (SEQ ID NO: 4); (e) a CDR-L2 comprising the amino acid sequence of AASRLQD (SEQ ID NO: 5); and (f) a CDR-L3 comprising the amino acid sequence of QQGSKYPLT (SEQ ID NO: 6).

[0345] In another example, provided herein is (a) a VH domain comprising an amino acid sequence having at least 90% sequence identity (e.g., at least 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% sequence identity) to the amino acid sequence of SEQ ID NO: 7, or the amino acid sequence of SEQ ID NO: 7; (b) a VL domain comprising an amino acid sequence having at least 90% sequence identity (e.g., at least 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% sequence identity) to the amino acid sequence of SEQ ID NO: 8, or the amino acid sequence of SEQ ID NO: 8; or (c) an anti-IL-33 antibody comprising the VH domain described in (a) and the VL domain described in (b).

[0346] Any of the anti-IL-33 antibodies provided herein may comprise the following heavy chain framework region: EVQLVX1SGX2X3X4X5X6PGX7SX8X9X 10 SCX 11 FR-H1 comprising the amino acid sequence of ASGFTFN (SEQ ID NO: 9), where X1 is E or Q; X2 is G or A; X3 is G or E; X4 is L or V; X5 is V or K; X6 is Q or K; X7 is G, A, or T; X8 is L or V; X9 is R or K; and X 10 is L or V; X 11 is A, K, or L; FR-H2 comprising the amino acid sequence of WX1RQAPGX2GLEWX3X4 (SEQ ID NO: 10) (wherein X1 is I or V; X2 is K or Q; X3 is V, M, or I; and X4 is A or G); RX1TX2X3RDX4X5X6X7X8X9YX 10 X 11 X 12 X 13 SLRX 14 EDTAX 15 FR-H3 comprising the amino acid sequence of YYCTR (SEQ ID NO: 11) (wherein X1 is F or V; X2 is I or M; X3 is S or T; X4 is D, N, or T; X5 is A or S; X6 is K or T; X7 is S or N; X8 is S or T; X9 is L or V; and X 10is L or M; X 11 is Q or E; X 12 is M or L; X 13 is N or S; X 14 is A or S; X 15 is V or T); and FR-H4 comprising the amino acid sequence of WGQGTLVTVSS (SEQ ID NO: 12), or a combination of one or more of the above FRs, and / or one or more variants thereof having at least about 80% sequence identity (e.g., 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identity) to any one of SEQ ID NOs: 9-12.

[0347] For example, in some instances, an anti-IL-33 antibody comprises the following heavy chain framework regions: FR-H1 comprising the amino acid sequence of EVQLVESGGGLVQPGGSLRLSCAASGFTFN (SEQ ID NO: 17); FR-H2 comprising the amino acid sequence of WIRQAPGKGLEWVA (SEQ ID NO: 18); FR-H3 comprising the amino acid sequence of RFTISRDDAKSSLYLQMNSLRAEDTAVYYCTR (SEQ ID NO: 19); and FR-H4 comprising the amino acid sequence of WGQGTLVTVSS (SEQ ID NO: 12). The FR-H4 may comprise one, two, three, or four of the FR-H4s comprising the amino acid sequence, or a combination of one or more of the above FRs, and / or one or more variants thereof having at least about 80% sequence identity (e.g., 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identity) to any one of SEQ ID NOs: 12 and 17-19. In some instances, an anti-IL-33 antibody may comprise one, two, three, or four of the following heavy chain framework regions: FR-H1 comprising the amino acid sequence of EVQLVESGGGLVQPGGSLRLSCAASGFTFN (SEQ ID NO: 17); FR-H2 comprising the amino acid sequence of WIRQAPGKGLEWVA (SEQ ID NO: 18); FR-H3 comprising the amino acid sequence of RFTISRDDAKSSLYLQMNSLRAEDTAVYYCTR (SEQ ID NO: 19); and FR-H4 comprising the amino acid sequence of WGQGTLVTVSS (SEQ ID NO: 12). In some embodiments, the VH domain comprises the amino acid sequence of SEQ ID NO: 7.

[0348] In another example, in some cases, the anti-IL-33 antibody comprises the following heavy chain framework regions: FR-H1 comprising the amino acid sequence of EVQLVESGGGLVQPGGSLRLSCAASGFTFN (SEQ ID NO: 17); FR-H2 comprising the amino acid sequence of WVRQAPGKGLEWVA (SEQ ID NO: 39); FR-H3 comprising the amino acid sequence of RFTISRDNAKNSLYLQMNSLRAEDTAVYYCTR (SEQ ID NO: 40); and FR-H4 comprising the amino acid sequence of WGQGTLVTVSS (SEQ ID NO: 12). The FR-H4 may comprise one, two, three, or four of the FR-H4s comprising the amino acid sequence, or a combination of one or more of the above FRs, and / or one or more variants thereof having at least about 80% sequence identity (e.g., 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identity) to any one of SEQ ID NOs: 12, 17, 39, and 40. In some instances, an anti-IL-33 antibody may comprise one, two, three, or four of the following heavy chain framework regions: FR-H1 comprising the amino acid sequence of EVQLVESGGGLVQPGGSLRLSCAASGFTFN (SEQ ID NO: 17); FR-H2 comprising the amino acid sequence of WVRQAPGKGLEWVA (SEQ ID NO: 39); FR-H3 comprising the amino acid sequence of RFTISRDNAKNSLYLQMNSLRAEDTAVYYCTR (SEQ ID NO: 40); and FR-H4 comprising the amino acid sequence of WGQGTLVTVSS (SEQ ID NO: 12). In some embodiments, the VH domain comprises the amino acid sequence of SEQ ID NO: 41.

[0349] In another example, in some cases, the anti-IL-33 antibody comprises the following heavy chain framework regions: FR-H1 comprising the amino acid sequence of EVQLVESGGGLVQPGGSLRLSCAASGFTFN (SEQ ID NO: 17); FR-H2 comprising the amino acid sequence of WIRQAPGKGLEWIA (SEQ ID NO: 42); FR-H3 comprising the amino acid sequence of RFTISRDDAKSSLYLQMNSLRAEDTAVYYCTR (SEQ ID NO: 19); and FR-H4 comprising the amino acid sequence of WGQGTLVTVSS (SEQ ID NO: 12). The FR-H4 may comprise one, two, three, or four of the FR-H4s comprising the amino acid sequence, or a combination of one or more of the above FRs, and / or one or more variants thereof having at least about 80% sequence identity (e.g., 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identity) to any one of SEQ ID NOs: 12, 17, 19, and 42. In some cases, an anti-IL-33 antibody may include one, two, three, or four of the following heavy chain framework regions: FR-H1 comprising the amino acid sequence of EVQLVESGGGLVQPGGSLRLSCAASGFTFN (SEQ ID NO: 17); FR-H2 comprising the amino acid sequence of WIRQAPGKGLEWIA (SEQ ID NO: 42); FR-H3 comprising the amino acid sequence of RFTISRDDAKSSLYLQMNSLRAEDTAVYYCTR (SEQ ID NO: 19); and FR-H4 comprising the amino acid sequence of WGQGTLVTVSS (SEQ ID NO: 12). In some cases, the VH domain comprises the amino acid sequence of SEQ ID NO: 43.

[0350] In another example, in some cases, the anti-IL-33 antibody comprises the following heavy chain framework regions: FR-H1 comprising the amino acid sequence of EVQLVESGGGLVQPGGSLRLSCAASGFTFN (SEQ ID NO: 17); FR-H2 comprising the amino acid sequence of WVRQAPGKGLEWVA (SEQ ID NO: 39); FR-H3 comprising the amino acid sequence of RFTISRDDAKSSLYLQMNSLRAEDTAVYYCTR (SEQ ID NO: 19); and FR-H4 comprising the amino acid sequence of WGQGTLVTVSS (SEQ ID NO: 12). The FR-H4 may comprise one, two, three, or four of the FR-H4s comprising the amino acid sequence, or a combination of one or more of the above FRs, and / or one or more variants thereof having at least about 80% sequence identity (e.g., 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identity) to any one of SEQ ID NOs: 12, 17, 19, and 39. In some cases, an anti-IL-33 antibody may include one, two, three, or four of the following heavy chain framework regions: FR-H1 comprising the amino acid sequence of EVQLVESGGGLVQPGGSLRLSCAASGFTFN (SEQ ID NO: 17); FR-H2 comprising the amino acid sequence of WVRQAPGKGLEWVA (SEQ ID NO: 39); FR-H3 comprising the amino acid sequence of RFTISRDDAKSSLYLQMNSLRAEDTAVYYCTR (SEQ ID NO: 19); and FR-H4 comprising the amino acid sequence of WGQGTLVTVSS (SEQ ID NO: 12). In some cases, the VH domain comprises the amino acid sequence of SEQ ID NO: 44.

[0351] In another example, in some cases, the anti-IL-33 antibody comprises the following heavy chain framework regions: FR-H1 comprising the amino acid sequence of EVQLVESGGGLVQPGGSLRLSCAASGFTFN (SEQ ID NO: 17); FR-H2 comprising the amino acid sequence of WVRQAPGKGLEWVA (SEQ ID NO: 39); FR-H3 comprising the amino acid sequence of RFTISRDDAKNSLYLQMNSLRAEDTAVYYCTR (SEQ ID NO: 45); and FR-H4 comprising the amino acid sequence of WGQGTLVTVSS (SEQ ID NO: 12). The FR-H4 may comprise one, two, three, or four of the FR-H4s comprising the amino acid sequence, or a combination of one or more of the above FRs, and / or one or more variants thereof having at least about 80% sequence identity (e.g., 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identity) to any one of SEQ ID NOs: 12, 17, 39, and 45. In some instances, an anti-IL-33 antibody may comprise one, two, three, or four of the following heavy chain framework regions: FR-H1 comprising the amino acid sequence of EVQLVESGGGLVQPGGSLRLSCAASGFTFN (SEQ ID NO: 17); FR-H2 comprising the amino acid sequence of WVRQAPGKGLEWVA (SEQ ID NO: 39); FR-H3 comprising the amino acid sequence of RFTISRDDAKNSLYLQMNSLRAEDTAVYYCTR (SEQ ID NO: 45); and FR-H4 comprising the amino acid sequence of WGQGTLVTVSS (SEQ ID NO: 12). In some embodiments, the VH domain comprises the amino acid sequence of SEQ ID NO: 46.

[0352] In another example, in some cases, the anti-IL-33 antibody comprises the following heavy chain framework regions: FR-H1 comprising the amino acid sequence of EVQLVESGGGLVQPGGSLRLSCAASGFTFN (SEQ ID NO: 17); FR-H2 comprising the amino acid sequence of WVRQAPGKGLEWVA (SEQ ID NO: 39); FR-H3 comprising the amino acid sequence of RFTISRDNAKSSLYLQMNSLRAEDTAVYYCTR (SEQ ID NO: 47); and FR-H4 comprising the amino acid sequence of WGQGTLVTVSS (SEQ ID NO: 12). The FR-H4 may comprise one, two, three, or four of the FR-H4s comprising the amino acid sequence, or a combination of one or more of the above FRs, and / or one or more variants thereof having at least about 80% sequence identity (e.g., 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identity) to any one of SEQ ID NOs: 12, 17, 39, and 47. In some instances, an anti-IL-33 antibody may comprise one, two, three, or four of the following heavy chain framework regions: FR-H1 comprising the amino acid sequence of EVQLVESGGGLVQPGGSLRLSCAASGFTFN (SEQ ID NO: 17); FR-H2 comprising the amino acid sequence of WVRQAPGKGLEWVA (SEQ ID NO: 39); FR-H3 comprising the amino acid sequence of RFTISRDNAKSSLYLQMNSLRAEDTAVYYCTR (SEQ ID NO: 47); and FR-H4 comprising the amino acid sequence of WGQGTLVTVSS (SEQ ID NO: 12). In some embodiments, the VH domain comprises the amino acid sequence of SEQ ID NO: 48.

[0353] In another example, in some cases, the anti-IL-33 antibody comprises the following heavy chain framework regions: FR-H1 comprising the amino acid sequence of EVQLVESGGGLVQPGGSLRLSCAASGFTFN (SEQ ID NO: 17); FR-H2 comprising the amino acid sequence of WVRQAPGKGLEWIA (SEQ ID NO: 49); FR-H3 comprising the amino acid sequence of RFTISRDDAKSSLYLQMNSLRAEDTAVYYCTR (SEQ ID NO: 19); and FR-H4 comprising the amino acid sequence of WGQGTLVTVSS (SEQ ID NO: 12). The FR-H4 may comprise one, two, three, or four of the FR-H4s comprising the amino acid sequence, or a combination of one or more of the above FRs, and / or one or more variants thereof having at least about 80% sequence identity (e.g., 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identity) to any one of SEQ ID NOs: 12, 17, 19, and 49. In some cases, an anti-IL-33 antibody may include one, two, three, or four of the following heavy chain framework regions: FR-H1 comprising the amino acid sequence of EVQLVESGGGLVQPGGSLRLSCAASGFTFN (SEQ ID NO: 17); FR-H2 comprising the amino acid sequence of WVRQAPGKGLEWIA (SEQ ID NO: 49); FR-H3 comprising the amino acid sequence of RFTISRDDAKSSLYLQMNSLRAEDTAVYYCTR (SEQ ID NO: 19); and FR-H4 comprising the amino acid sequence of WGQGTLVTVSS (SEQ ID NO: 12). In some cases, the VH domain comprises the amino acid sequence of SEQ ID NO: 50.

[0354] In another example, in some cases, the anti-IL-33 antibody comprises the following heavy chain framework regions: FR-H1 comprising the amino acid sequence of EVQLVESGGGLVQPGGSLRLSCAASGFTFN (SEQ ID NO: 17); FR-H2 comprising the amino acid sequence of WVRQAPGKGLEWIA (SEQ ID NO: 49); FR-H3 comprising the amino acid sequence of RFTISRDDSKSTLYLQMNSLRAEDTAVYYCTR (SEQ ID NO: 51); and FR-H4 comprising the amino acid sequence of WGQGTLVTVSS (SEQ ID NO: 12). The FR-H4 may comprise one, two, three, or four of the FR-H4s comprising the amino acid sequence, or a combination of one or more of the above FRs, and / or one or more variants thereof having at least about 80% sequence identity (e.g., 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identity) to any one of SEQ ID NOs: 12, 17, 49, and 51. In some cases, an anti-IL-33 antibody may include one, two, three, or four of the following heavy chain framework regions: FR-H1 comprising the amino acid sequence of EVQLVESGGGLVQPGGSLRLSCAASGFTFN (SEQ ID NO: 17); FR-H2 comprising the amino acid sequence of WVRQAPGKGLEWIA (SEQ ID NO: 49); FR-H3 comprising the amino acid sequence of RFTISRDDSKSTLYLQMNSLRAEDTAVYYCTR (SEQ ID NO: 51); and FR-H4 comprising the amino acid sequence of WGQGTLVTVSS (SEQ ID NO: 12). In some cases, the VH domain comprises the amino acid sequence of SEQ ID NO: 52.

[0355] Any of the anti-IL-33 antibodies provided herein may comprise the following light chain framework region: X1IX2X3TQSPX4X5LSX6SX7GX8X9X 10 X 11 X 12 X 13 FR-L1 comprising the amino acid sequence of X1, X2, X3, X4, X5, X6, X7, X8, X9, X10, X11, X12, X13, X14, X15, X16, X17, X18, X19, X20, X21, X22, X23, X24, X25, X26, X27, X28, X29, X30, X31, X32, X33, X34, X35, X36, X37, X38, X39, X40, X41, X42, X43, X44, X45, X46, X47, X48, X49, X50, X51, X52, X53, X54, X55, X56, X57, X58, X59, X60, X61, X62, X63, X64, X65, X66, X67, X68, X69, X70, X71, X72, X73, X74, X75, X76, X77, X78, X79, X80, X81, X82, X83, X84, X85, X86, X87, X88, X89, X90, X91, X92, X93, X94, X95, X96, X97, X98, X99, X99, X91, X95, X96, X97, X98, X99, X99, X99, X100, X101, X110, X111, X121, X122, X123, X124, X125, X130, X131, X132, X141, X142, X143, X110 is V or A; X 11 is T or S; X 12 is I or L; X 13 is T, S, or E); FR-L2 comprising the amino acid sequence of WX1QQKX2GX3X4PX5X6LIY (SEQ ID NO: 14) (wherein X1 is Y or F; X2 is P or S; X3 is K or Q; X4 is S or A; X5 is K, R, or Q; and X6 is L or S); GX1PX2RFSGSGSGTX3FX4LX5ISX6X7X8PEDX9AX 10 YX 11 FR-L3 comprising the amino acid sequence of X1, X2, X3, X4, X5, X6, X7, X8, X9, X10, X11, X12, X13, X14, X15, X16, X17, X18, X19, X20, X21, X22, X23, X24, X25, X26, X27, X28, X29, X30, X31, X32, X33, X34, X35, X36, X37, X38, X39, X40, X41, X42, X43, X44, X45, X46, X47, X48, X49, X50, X51, X52, X53, X54, X55, X56, X57, X58, X59, X60, X61, X62, X63, X64, X65, X66, X77, X78, X79, X81, X82, X83, X84, X85, X86, X87, X88, X89, X90, X91, X92, X93, X94, X95, X96, X97, X98, X99, X99, X91, X92, X94, X95, X95, X96, X97, X98, X99, X99, X99, X99, X100, X101, X110, X111, X121, X122, X123, X124, X125, X126, X127, X128, X129, X130, X131, X132, X141, X142, X143, X144, X145, 10 is T, V, or D; X 11 is F or Y); and FR-L4 comprising the amino acid sequence of FGX1GTKX2EIK (SEQ ID NO: 16) (wherein X1 is G or S and X2 is V or L), or a combination of one or more of the above FRs, and / or one or more variants thereof having at least about 80% sequence identity (e.g., 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identity) to any one of SEQ ID NOs: 13-16. In some cases, the anti-IL-33 antibody may comprise one, two, three, or four of the following: X1IX2X3TQSPX4X5LSX6SX7GX8X9X 10 X 11 X 12 X 13 FR-L1 comprising the amino acid sequence of X1, X2, X3, X4, X5, X6, X7, X8, X9, X10, X11, X12, X13, X14, X15, X16, X17, X18, X19, X20, X21, X22, X23, X24, X25, X26, X27, X28, X29, X30, X31, X32, X33, X34, X35, X36, X37, X38, X39, X40, X41, X42, X43, X44, X45, X46, X47, X48, X49, X50, X51, X52, X53, X54, X55, X56, X57, X58, X59, X60, X61, X62, X63, X64, X65, X66, X67, X68, X69, X70, X71, X72, X73, X74, X75, X76, X77, X78, X79, X80, X81, X82, X83, X84, X85, X86, X87, X88, X89, X90, X91, X92, X93, X94, X95, X96, X97, X98, X99, X99, X91, X95, X96, X97, X98, X99, X99, X99, X100, X101, X110, X111, X121, X122, X123, X124, X125, X130, X131, X132, X141, X142, X143, X1 10 is V or A; X 11 is T or S; X12 is I or L; X 13 is T, S, or E); FR-L2 comprising the amino acid sequence of WX1QQKX2GX3X4PX5X6LIY (SEQ ID NO: 14) (wherein X1 is Y or F; X2 is P or S; X3 is K or Q; X4 is S or A; X5 is K, R, or Q; and X6 is L or S); GX1PX2RFSGSGSGTX3FX4LX5ISX6X7X8PEDX9AX 10 YX 11 FR-L3 comprising the amino acid sequence of X1, X2, X3, X4, X5, X6, X7, X8, X9, X10, X11, X12, X13, X14, X15, X16, X17, X18, X19, X20, X21, X22, X23, X24, X25, X26, X27, X28, X29, X30, X31, X32, X33, X34, X35, X36, X37, X38, X39, X40, X41, X42, X43, X44, X45, X46, X47, X48, X49, X50, X51, X52, X53, X54, X55, X56, X57, X58, X59, X60, X61, X62, X63, X64, X65, X66, X77, X78, X79, X81, X82, X83, X84, X85, X86, X87, X88, X89, X90, X91, X92, X93, X94, X95, X96, X97, X98, X99, X99, X91, X92, X94, X95, X95, X96, X97, X98, X99, X99, X99, X99, X100, X101, X110, X111, X121, X122, X123, X124, X125, X126, X127, X128, X129, X130, X131, X132, X141, X142, X143, X144, X145, 10 is T, V, or D; X 11 is F or Y); and FR-L4 (wherein X1 is G or S and X2 is V or L) comprising the amino acid sequence of FGX1GTKX2EIK (SEQ ID NO: 16).

[0356] For example, in some instances, an anti-IL-33 antibody comprises the following light chain framework regions: FR-L1 comprising the amino acid sequence of DIQMTQSPSSLSASVGDRVTITC (SEQ ID NO: 21); FR-L2 comprising the amino acid sequence of WYQQKPGKSPKLLIY (SEQ ID NO: 22); FR-L3 comprising the amino acid sequence of GVPSRFSGSGSGTDFTLTISSLQPEDFATYFC (SEQ ID NO: 23); and FR-L4 comprising the amino acid sequence of FGGGTKVEIK (SEQ ID NO: 24). The FR-L4 may comprise one, two, three, or four of the FR-L4s comprising the amino acid sequence, or a combination of one or more of the above FRs, and / or one or more variants thereof having at least about 80% sequence identity (e.g., 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identity) to any one of SEQ ID NOs: 21-24. In some cases, an anti-IL-33 antibody may include one, two, three, or four of the following light chain framework regions: FR-L1 comprising the amino acid sequence of DIQMTQSPSSLSASVGDRVTITC (SEQ ID NO: 21); FR-L2 comprising the amino acid sequence of WYQQKPGKSPKLLIY (SEQ ID NO: 22); FR-L3 comprising the amino acid sequence of GVPSRFSGSGSGTDFTLTISSLQPEDFATYFC (SEQ ID NO: 23); and FR-L4 comprising the amino acid sequence of FGGGTKVEIK (SEQ ID NO: 24). In some cases, the VL domain comprises the amino acid sequence of SEQ ID NO: 8.

[0357] For example, an anti-IL-33 antibody may comprise: (a) a CDR-H1 comprising the amino acid sequence of NYWMT (SEQ ID NO: 1); (b) a CDR-H2 comprising the amino acid sequence of SITYTGGGTYYPDSVKG (SEQ ID NO: 2); (c) a CDR-H3 comprising the amino acid sequence of ANYYYNTYGGFPY (SEQ ID NO: 3); (d) a CDR-L1 comprising the amino acid sequence of LASEGFSNDLA (SEQ ID NO: 4); (e) a CDR-L2 comprising the amino acid sequence of AASRLQD (SEQ ID NO: 5); and (f) a CDR-L3 comprising the amino acid sequence of QQGSKYPLT (SEQ ID NO: 6). In some cases, the anti-IL-33 antibody comprises: (a) a heavy chain variable (VH) domain comprising an amino acid sequence having at least 90% sequence identity (e.g., at least 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% sequence identity) to SEQ ID NO: 7, or the sequence of SEQ ID NO: 7; (b) a light chain variable (VL) domain comprising an amino acid sequence having at least 90% sequence identity (e.g., at least 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% sequence identity) to SEQ ID NO: 8, or the sequence of SEQ ID NO: 8; or (c) a VH domain described in (a) and a VL domain described in (b). In some instances, the anti-IL-33 antibody comprises the following heavy chain framework regions: FR-H1 comprising the amino acid sequence of EVQLVESGGGLVQPGGSLRLSCAASGFTFN (SEQ ID NO: 17); FR-H2 comprising the amino acid sequence of WIRQAPGKGLEWVA (SEQ ID NO: 18); FR-H3 comprising the amino acid sequence of RFTISRDDAKSSLYLQMNSLRAEDTAVYYCTR (SEQ ID NO: 19); and FR-H4 comprising the amino acid sequence of WGQGTLVTVSS (SEQ ID NO: 12). In some instances, the anti-IL-33 antibody comprises the following light chain framework regions: FR-L1 comprising the amino acid sequence of DIQMTQSPSSLSASVGDRVTITC (SEQ ID NO: 21); FR-L2 comprising the amino acid sequence of WYQQKPGKSPKLLIY (SEQ ID NO: 22); FR-L3 comprising the amino acid sequence of GVPSRFSGSGSGTDFTLTISSLQPEDFATYFC (SEQ ID NO: 23); and FR-L4 comprising the amino acid sequence of FGGGTKVEIK (SEQ ID NO: 24).In some instances, the anti-IL-33 antibody comprises a binding domain comprising (a) a VH domain comprising the amino acid sequence of SEQ ID NO: 7 and (b) a VL domain comprising the amino acid sequence of SEQ ID NO: 8. In some instances, an exemplary anti-IL-33 antibody is 1E1v8.

[0358] For example, provided herein is an isolated antibody, or antigen-binding fragment thereof, that specifically binds to IL-33, wherein the antibody comprises (a) a VH domain comprising the amino acid sequence of SEQ ID NO:7 and (b) a VL domain comprising the amino acid sequence of SEQ ID NO:8.

[0359] In another example, provided herein is an isolated antibody, or antigen-binding fragment thereof, that specifically binds to IL-33, wherein the antibody comprises (a) a heavy chain (HC) comprising the amino acid sequence of SEQ ID NO:25 and (b) a light chain (LC) comprising the amino acid sequence of SEQ ID NO:26.

[0360] In another example, in some cases, the anti-IL-33 antibody comprises the following light chain framework regions: FR-L1 comprising the amino acid sequence of DIQMTQSPSSLSASVGDRVTITC (SEQ ID NO: 21); FR-L2 comprising the amino acid sequence of WFQQKPGKAPKSLIY (SEQ ID NO: 53); FR-L3 comprising the amino acid sequence of GVPSRFSGSGSGTDFTLTISSLQPEDFATYYC (SEQ ID NO: 54); and FR-L4 comprising the amino acid sequence of FGGGTKVEIK (SEQ ID NO: 24). or a combination of one or more of the above FRs, and / or one or more variants thereof having at least about 80% sequence identity (e.g., 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identity) to any one of SEQ ID NOs: 21, 24, 53, and 54. In some cases, an anti-IL-33 antibody may comprise one, two, three, or four of the following light chain framework regions: FR-L1 comprising the amino acid sequence of DIQMTQSPSSLSASVGDRVTITC (SEQ ID NO: 21); FR-L2 comprising the amino acid sequence of WFQQKPGKAPKSLIY (SEQ ID NO: 53); FR-L3 comprising the amino acid sequence of GVPSRFSGSGSGTDFTLTISSLQPEDFATYYC (SEQ ID NO: 54); and FR-L4 comprising the amino acid sequence of FGGGTKVEIK (SEQ ID NO: 24). In some cases, the VL domain comprises the amino acid sequence of SEQ ID NO: 55.

[0361] In another example, in some cases, the anti-IL-33 antibody comprises the following light chain framework regions: FR-L1 comprising the amino acid sequence of DIQMTQSPSSLSASVGDRVTITC (SEQ ID NO: 21); FR-L2 comprising the amino acid sequence of WYQQKPGKAPKSLIY (SEQ ID NO: 56); FR-L3 comprising the amino acid sequence of GVPSRFSGSGSGTDFTLTISSLQPEDFATYFC (SEQ ID NO: 23); and FR-L4 comprising the amino acid sequence of FGGGTKVEIK (SEQ ID NO: 24). or a combination of one or more of the above FRs, and / or one or more variants thereof having at least about 80% sequence identity (e.g., 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identity) to any one of SEQ ID NOs: 21, 23, 24, and 56. In some cases, an anti-IL-33 antibody may comprise one, two, three, or four of the following light chain framework regions: FR-L1 comprising the amino acid sequence of DIQMTQSPSSLSASVGDRVTITC (SEQ ID NO: 21); FR-L2 comprising the amino acid sequence of WYQQKPGKAPKSLIY (SEQ ID NO: 56); FR-L3 comprising the amino acid sequence of GVPSRFSGSGSGTDFTLTISSLQPEDFATYFC (SEQ ID NO: 23); and FR-L4 comprising the amino acid sequence of FGGGTKVEIK (SEQ ID NO: 24). In some cases, the VL domain comprises the amino acid sequence of SEQ ID NO: 57.

[0362] In another example, in some cases, the anti-IL-33 antibody comprises the following light chain framework regions: FR-L1 comprising the amino acid sequence of DIQMTQSPSSLSASVGDRVTITC (SEQ ID NO: 21); FR-L2 comprising the amino acid sequence of WFQQKPGKAPKSLIY (SEQ ID NO: 53); FR-L3 comprising the amino acid sequence of GVPSRFSGSGSGTDFTLTISSLQPEDFATYFC (SEQ ID NO: 23); and FR-L4 comprising the amino acid sequence of FGGGTKVEIK (SEQ ID NO: 24). or a combination of one or more of the above FRs, and / or one or more variants thereof having at least about 80% sequence identity (e.g., 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identity) to any one of SEQ ID NOs: 21, 23, 24, and 53. In some cases, an anti-IL-33 antibody may include one, two, three, or four of the following light chain framework regions: FR-L1 comprising the amino acid sequence of DIQMTQSPSSLSASVGDRVTITC (SEQ ID NO: 21); FR-L2 comprising the amino acid sequence of WFQQKPGKAPKSLIY (SEQ ID NO: 53); FR-L3 comprising the amino acid sequence of GVPSRFSGSGSGTDFTLTISSLQPEDFATYFC (SEQ ID NO: 23); and FR-L4 comprising the amino acid sequence of FGGGTKVEIK (SEQ ID NO: 24). In some cases, the VL domain comprises the amino acid sequence of SEQ ID NO: 58.

[0363] In another example, in some cases, the anti-IL-33 antibody comprises the following light chain framework regions: FR-L1 comprising the amino acid sequence of DIQMTQSPSSLSASVGDRVTITC (SEQ ID NO: 21); FR-L2 comprising the amino acid sequence of WYQQKPGKAPKSLIY (SEQ ID NO: 56); FR-L3 comprising the amino acid sequence of GVPSRFSGSGSGTDFTLTISSLQPEDFATYYC (SEQ ID NO: 54); and FR-L4 comprising the amino acid sequence of FGGGTKVEIK (SEQ ID NO: 24). or a combination of one or more of the above FRs, and / or one or more variants thereof having at least about 80% sequence identity (e.g., 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identity) to any one of SEQ ID NOs: 21, 24, 54, and 56. In some cases, an anti-IL-33 antibody may comprise one, two, three, or four of the following light chain framework regions: FR-L1 comprising the amino acid sequence of DIQMTQSPSSLSASVGDRVTITC (SEQ ID NO: 21); FR-L2 comprising the amino acid sequence of WYQQKPGKAPKSLIY (SEQ ID NO: 56); FR-L3 comprising the amino acid sequence of GVPSRFSGSGSGTDFTLTISSLQPEDFATYYC (SEQ ID NO: 54); and FR-L4 comprising the amino acid sequence of FGGGTKVEIK (SEQ ID NO: 24). In some cases, the VL domain comprises the amino acid sequence of SEQ ID NO: 59.

[0364] In another example, in some cases, the anti-IL-33 antibody comprises the following light chain framework regions: FR-L1 comprising the amino acid sequence of DIQMTQSPSSLSASVGDRVTITC (SEQ ID NO: 21); FR-L2 comprising the amino acid sequence of WYQQKPGKSPKLLIY (SEQ ID NO: 22); FR-L3 comprising the amino acid sequence of GVPSRFSGSGSGTDFTLTISSLQPEDVATYYC (SEQ ID NO: 60); and FR-L4 comprising the amino acid sequence of FGGGTKVEIK (SEQ ID NO: 24). or a combination of one or more of the above FRs, and / or one or more variants thereof having at least about 80% sequence identity (e.g., 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identity) to any one of SEQ ID NOs: 21, 22, 24, and 60. In some cases, an anti-IL-33 antibody may comprise one, two, three, or four of the following light chain framework regions: FR-L1 comprising the amino acid sequence of DIQMTQSPSSLSASVGDRVTITC (SEQ ID NO: 21); FR-L2 comprising the amino acid sequence of WYQQKPGKSPKLLIY (SEQ ID NO: 22); FR-L3 comprising the amino acid sequence of GVPSRFSGSGSGTDFTLTISSLQPEDVATYYC (SEQ ID NO: 60); and FR-L4 comprising the amino acid sequence of FGGGTKVEIK (SEQ ID NO: 24). In some cases, the VL domain comprises the amino acid sequence of SEQ ID NO: 61.

[0365] For example, provided herein is an isolated antibody, or antigen-binding fragment thereof, that specifically binds to IL-33, wherein the antibody comprises (a) a VH domain comprising the amino acid sequence of SEQ ID NO: 41 and (b) a VL domain comprising the amino acid sequence of SEQ ID NO: 55.

[0366] In another example, provided herein is an isolated antibody, or antigen-binding fragment thereof, that specifically binds to IL-33, wherein the antibody comprises (a) a VH domain comprising the amino acid sequence of SEQ ID NO: 43 and (b) a VL domain comprising the amino acid sequence of SEQ ID NO: 55.

[0367] In another example, provided herein is an isolated antibody, or antigen-binding fragment thereof, that specifically binds to IL-33, wherein the antibody comprises (a) a VH domain comprising the amino acid sequence of SEQ ID NO: 41 and (b) a VL domain comprising the amino acid sequence of SEQ ID NO: 8.

[0368] In another example, provided herein is an isolated antibody, or antigen-binding fragment thereof, that specifically binds to IL-33, wherein the antibody comprises (a) a VH domain comprising the amino acid sequence of SEQ ID NO: 43 and (b) a VL domain comprising the amino acid sequence of SEQ ID NO: 8.

[0369] In another example, provided herein is an isolated antibody, or antigen-binding fragment thereof, that specifically binds to IL-33, wherein the antibody comprises (a) a VH domain comprising the amino acid sequence of SEQ ID NO: 44 and (b) a VL domain comprising the amino acid sequence of SEQ ID NO: 8.

[0370] In another example, provided herein is an isolated antibody, or antigen-binding fragment thereof, that specifically binds to IL-33, wherein the antibody comprises (a) a VH domain comprising the amino acid sequence of SEQ ID NO: 46 and (b) a VL domain comprising the amino acid sequence of SEQ ID NO: 8.

[0371] In another example, provided herein is an isolated antibody, or antigen-binding fragment thereof, that specifically binds to IL-33, wherein the antibody comprises (a) a VH domain comprising the amino acid sequence of SEQ ID NO: 48 and (b) a VL domain comprising the amino acid sequence of SEQ ID NO: 8.

[0372] In another example, provided herein is an isolated antibody, or antigen-binding fragment thereof, that specifically binds to IL-33, wherein the antibody comprises (a) a VH domain comprising the amino acid sequence of SEQ ID NO: 43 and (b) a VL domain comprising the amino acid sequence of SEQ ID NO: 57.

[0373] In another example, provided herein is an isolated antibody, or antigen-binding fragment thereof, that specifically binds to IL-33, wherein the antibody comprises (a) a VH domain comprising the amino acid sequence of SEQ ID NO: 44 and (b) a VL domain comprising the amino acid sequence of SEQ ID NO: 57.

[0374] In another example, provided herein is an isolated antibody, or antigen-binding fragment thereof, that specifically binds to IL-33, wherein the antibody comprises (a) a VH domain comprising the amino acid sequence of SEQ ID NO: 46 and (b) a VL domain comprising the amino acid sequence of SEQ ID NO: 57.

[0375] In another example, provided herein is an isolated antibody, or antigen-binding fragment thereof, that specifically binds to IL-33, wherein the antibody comprises (a) a VH domain comprising the amino acid sequence of SEQ ID NO: 48 and (b) a VL domain comprising the amino acid sequence of SEQ ID NO: 57.

[0376] In another example, provided herein is an isolated antibody, or antigen-binding fragment thereof, that specifically binds to IL-33, wherein the antibody comprises (a) a VH domain comprising the amino acid sequence of SEQ ID NO: 50 and (b) a VL domain comprising the amino acid sequence of SEQ ID NO: 57.

[0377] In another example, provided herein is an isolated antibody, or antigen-binding fragment thereof, that specifically binds to IL-33, wherein the antibody comprises (a) a VH domain comprising the amino acid sequence of SEQ ID NO: 43 and (b) a VL domain comprising the amino acid sequence of SEQ ID NO: 58.

[0378] In another example, provided herein is an isolated antibody, or antigen-binding fragment thereof, that specifically binds to IL-33, wherein the antibody comprises (a) a VH domain comprising the amino acid sequence of SEQ ID NO: 44 and (b) a VL domain comprising the amino acid sequence of SEQ ID NO: 58.

[0379] In another example, provided herein is an isolated antibody, or antigen-binding fragment thereof, that specifically binds to IL-33, wherein the antibody comprises (a) a VH domain comprising the amino acid sequence of SEQ ID NO: 46 and (b) a VL domain comprising the amino acid sequence of SEQ ID NO: 58.

[0380] In another example, provided herein is an isolated antibody, or antigen-binding fragment thereof, that specifically binds to IL-33, wherein the antibody comprises (a) a VH domain comprising the amino acid sequence of SEQ ID NO: 48 and (b) a VL domain comprising the amino acid sequence of SEQ ID NO: 58.

[0381] In another example, provided herein is an isolated antibody, or antigen-binding fragment thereof, that specifically binds to IL-33, wherein the antibody comprises (a) a VH domain comprising the amino acid sequence of SEQ ID NO: 50 and (b) a VL domain comprising the amino acid sequence of SEQ ID NO: 58.

[0382] In another example, provided herein is an isolated antibody, or antigen-binding fragment thereof, that specifically binds to IL-33, wherein the antibody comprises (a) a VH domain comprising the amino acid sequence of SEQ ID NO: 43 and (b) a VL domain comprising the amino acid sequence of SEQ ID NO: 59.

[0383] In another example, provided herein is an isolated antibody, or antigen-binding fragment thereof, that specifically binds to IL-33, wherein the antibody comprises (a) a VH domain comprising the amino acid sequence of SEQ ID NO: 44 and (b) a VL domain comprising the amino acid sequence of SEQ ID NO: 59.

[0384] In another example, provided herein is an isolated antibody, or antigen-binding fragment thereof, that specifically binds to IL-33, wherein the antibody comprises (a) a VH domain comprising the amino acid sequence of SEQ ID NO: 46 and (b) a VL domain comprising the amino acid sequence of SEQ ID NO: 59.

[0385] In another example, provided herein is an isolated antibody, or antigen-binding fragment thereof, that specifically binds to IL-33, wherein the antibody comprises (a) a VH domain comprising the amino acid sequence of SEQ ID NO: 48 and (b) a VL domain comprising the amino acid sequence of SEQ ID NO: 59.

[0386] In another example, provided herein is an isolated antibody, or antigen-binding fragment thereof, that specifically binds to IL-33, wherein the antibody comprises (a) a VH domain comprising the amino acid sequence of SEQ ID NO:50 and (b) a VL domain comprising the amino acid sequence of SEQ ID NO:59.

[0387] In another example, provided herein is an isolated antibody, or antigen-binding fragment thereof, that specifically binds to IL-33, wherein the antibody comprises (a) a VH domain comprising the amino acid sequence of SEQ ID NO: 52 and (b) a VL domain comprising the amino acid sequence of SEQ ID NO: 61.

[0388] In another example, provided herein is (a) a VH domain comprising an amino acid sequence having at least 90% sequence identity (e.g., at least 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% sequence identity) to the amino acid sequence of SEQ ID NO: 35, or the amino acid sequence of SEQ ID NO: 35; (b) a VL domain comprising an amino acid sequence having at least 90% sequence identity (e.g., at least 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% sequence identity) to the amino acid sequence of SEQ ID NO: 36, or the amino acid sequence of SEQ ID NO: 36; or (c) an anti-IL-33 antibody comprising the VH domain described in (a) and the VL domain described in (b).

[0389] In another example, in some cases, the anti-IL-33 antibody comprises the following heavy chain framework regions: FR-H1 comprising the amino acid sequence of EVQLVESGGGLVQPGTSLKLSCLASGFTFN (SEQ ID NO: 27); FR-H2 comprising the amino acid sequence of WIRQAPGKGLEWIA (SEQ ID NO: 28); FR-H3 comprising the amino acid sequence of RFTISRDDAKSTLYLQMNSLRSEDTATYYCTR (SEQ ID NO: 29); and FR-H4 comprising the amino acid sequence of WGQGTLVTVSS (SEQ ID NO: 12). The FR-H4 may comprise one, two, three, or four of the FR-H4s comprising the amino acid sequence, or a combination of one or more of the above FRs, and / or one or more variants thereof having at least about 80% sequence identity (e.g., 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identity) to any one of SEQ ID NOs: 12, 27, 28, and 29. In some cases, an anti-IL-33 antibody may include one, two, three, or four of the following heavy chain framework regions: FR-H1 comprising the amino acid sequence of EVQLVESGGGLVQPGTSLKLSCLASGFTFN (SEQ ID NO: 27); FR-H2 comprising the amino acid sequence of WIRQAPGKGLEWIA (SEQ ID NO: 28); FR-H3 comprising the amino acid sequence of RFTISRDDAKSTLYLQMNSLRSEDTATYYCTR (SEQ ID NO: 29); and FR-H4 comprising the amino acid sequence of WGQGTLVTVSS (SEQ ID NO: 12). In some cases, the VH domain comprises the amino acid sequence of SEQ ID NO: 35.

[0390] In another example, in some cases, the anti-IL-33 antibody comprises the following light chain framework regions: FR-L1 comprising the amino acid sequence of DIQMTQSPASLSASLGETVSIEC (SEQ ID NO: 31); FR-L2 comprising the amino acid sequence of WYQQKSGKSPQLLIY (SEQ ID NO: 32); FR-L3 comprising the amino acid sequence of GVPSRFSGSGSGTRFSLKISGMQPEDEADYFC (SEQ ID NO: 33); and FR-L4 comprising the amino acid sequence of FGSGTKLEIK (SEQ ID NO: 34). The FR-L4 may comprise one, two, three, or four of the FR-L4s comprising the amino acid sequence, or a combination of one or more of the above FRs, and / or one or more variants thereof having at least about 80% sequence identity (e.g., 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identity) to any one of SEQ ID NOs: 31-34. In some cases, an anti-IL-33 antibody may include one, two, three, or four of the following light chain framework regions: FR-L1 comprising the amino acid sequence of DIQMTQSPASLSASLGETVSIEC (SEQ ID NO: 31); FR-L2 comprising the amino acid sequence of WYQQKSGKSPQLLIY (SEQ ID NO: 32); FR-L3 comprising the amino acid sequence of GVPSRFSGSGSGTRFSLKISGMQPEDEADYFC (SEQ ID NO: 33); and FR-L4 comprising the amino acid sequence of FGSGTKLEIK (SEQ ID NO: 34). In some cases, the VL domain comprises the amino acid sequence of SEQ ID NO: 36.

[0391] For example, provided herein is an isolated antibody, or antigen-binding fragment thereof, that specifically binds to IL-33, wherein the antibody comprises (a) a VH domain comprising the amino acid sequence of SEQ ID NO: 35 and (b) a VL domain comprising the amino acid sequence of SEQ ID NO: 36.

[0392] For example, provided herein is an isolated antibody that specifically binds to IL-33, wherein the antibody comprises (a) a heavy chain (HC) comprising the amino acid sequence of SEQ ID NO: 37 and (b) a light chain (LC) comprising the amino acid sequence of SEQ ID NO: 38.

[0393] In another example, provided herein is (a) a VH domain comprising an amino acid sequence having at least 90% sequence identity (e.g., at least 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% sequence identity) to the amino acid sequence of SEQ ID NO: 65, or the amino acid sequence of SEQ ID NO: 65; (b) a VL domain comprising an amino acid sequence having at least 90% sequence identity (e.g., at least 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% sequence identity) to the amino acid sequence of SEQ ID NO: 69, or the amino acid sequence of SEQ ID NO: 69; or (c) an anti-IL-33 antibody comprising the VH domain described in (a) and the VL domain described in (b).

[0394] In another example, in some cases, the anti-IL-33 antibody comprises the following heavy chain framework regions: FR-H1 comprising the amino acid sequence of EVQLVQSGAEVKKPGASVKVSCKASGFTFN (SEQ ID NO: 62); FR-H2 comprising the amino acid sequence of WVRQAPGQGLEWMG (SEQ ID NO: 63); FR-H3 comprising the amino acid sequence of RVTMTRDTSTSTVYMELSSLRSEDTAVYYCTR (SEQ ID NO: 64); and FR-H4 comprising the amino acid sequence of WGQGTLVTVSS (SEQ ID NO: 12). The FR-H4 may comprise one, two, three, or four of the amino acid sequences, or a combination of one or more of the above FRs, and / or one or more variants thereof having at least about 80% sequence identity (e.g., 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identity) to any one of SEQ ID NOs: 12 and 62-64. In some cases, an anti-IL-33 antibody may include one, two, three, or four of the following heavy chain framework regions: FR-H1 comprising the amino acid sequence of EVQLVQSGAEVKKPGASVKVSCKASGFTFN (SEQ ID NO: 62); FR-H2 comprising the amino acid sequence of WVRQAPGQGLEWMG (SEQ ID NO: 63); FR-H3 comprising the amino acid sequence of RVTMTRDTSTSTVYMELSSLRSEDTAVYYCTR (SEQ ID NO: 64); and FR-H4 comprising the amino acid sequence of WGQGTLVTVSS (SEQ ID NO: 12). In some cases, the VH domain comprises the amino acid sequence of SEQ ID NO: 65.

[0395] In another example, in some cases, the anti-IL-33 antibody comprises the following light chain framework regions: FR-L1 comprising the amino acid sequence of EIVLTQSPATLSLSPGERATLSC (SEQ ID NO: 66); FR-L2 comprising the amino acid sequence of WYQQKPGQAPRLLIY (SEQ ID NO: 67); FR-L3 comprising the amino acid sequence of GIPARFSGSGSGTDFTLTISSLEPEDFAVYYC (SEQ ID NO: 68); and FR-L4 comprising the amino acid sequence of FGGGTKVEIK (SEQ ID NO: 24). The FR-L4 may comprise one, two, three, or four of the FR-L4s comprising the amino acid sequence, or a combination of one or more of the above FRs, and / or one or more variants thereof having at least about 80% sequence identity (e.g., 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identity) to any one of SEQ ID NOs: 24 and 66-68. In some cases, an anti-IL-33 antibody may include one, two, three, or four of the following light chain framework regions: FR-L1 comprising the amino acid sequence of EIVLTQSPATLSLSPGERATLSC (SEQ ID NO: 66); FR-L2 comprising the amino acid sequence of WYQQKPGQAPRLLIY (SEQ ID NO: 67); FR-L3 comprising the amino acid sequence of GIPARFSGSGSGTDFTLTISSLEPEDFAVYYC (SEQ ID NO: 68); and FR-L4 comprising the amino acid sequence of FGGGTKVEIK (SEQ ID NO: 24). In some cases, the VL domain comprises the amino acid sequence of SEQ ID NO: 69.

[0396] For example, provided herein is an isolated antibody, or antigen-binding fragment thereof, that specifically binds to IL-33, wherein the antibody comprises (a) a VH domain comprising the amino acid sequence of SEQ ID NO: 65 and (b) a VL domain comprising the amino acid sequence of SEQ ID NO: 69.

[0397] Any of the antibodies provided herein may specifically bind to human or cynomolgus monkey (cyno) IL-33. In some cases, the antibody specifically binds to both human and cyno IL-33. In certain cases, the anti-IL-33 antibodies provided herein have a K of 100 nM or less (e.g., 100 nM or less, 10 nM or less, 1 nM or less, 100 pM or less, 10 pM or less, 1 pM or less, or 0.1 pM or less). D It specifically binds to both human and cyno IL-33.

[0398] In some cases, the antibody has a K of 1 nM or less (e.g., 1 nm or less, 100 pM or less, 10 pM or less, 1 pM or less, or 0.1 pM or less). D For example, in some cases, the antibody specifically binds to human IL-33 with a K between 100 fM and 1 nM. D For example, in some cases, the antibody specifically binds to human IL-33 with a K between 100 fM and 1 nM. D In another example, in some cases, the antibody specifically binds to human IL-33 with a K between 750 fM and 300 pM. D In another example, the antibody specifically binds to human IL-33 with a K between 1 pM and 200 pM. D In some instances, the antibody specifically binds to human IL-33 with a K of 118 pM. D In other instances, the antibody specifically binds to human IL-33 with a K of 15 pM. D It specifically binds to human IL-33.

[0399] In some cases, the antibody has a K of 1 nM or less (e.g., 1 nm or less, 100 pM or less, 10 pM or less, 1 pM or less, or 0.1 pM or less). D For example, in some cases, the antibody specifically binds to cytoplasmic IL-33 with a K between 100 fM and 1 nM. D In another example, the antibody specifically binds to cyno IL-33 with a K between 1 pM and 500 pM. DIn another example, the antibody specifically binds to cyno IL-33 with a K between 20 pM and 50 pM. D In some instances, the antibody specifically binds to cyno IL-33 with a K of 35 pM. D It specifically binds to cyno IL-33.

[0400] In certain cases, the antibody has a K of 1 nM or less (e.g., 1 nM or less, 100 pM or less, 10 pM or less, 1 pM or less, or 0.1 pM or less). D For example, in some cases, the antibody specifically binds to both human and cyno IL-33 with a K between 1 pM and 500 pM. D In some cases, the antibody specifically binds to both human and cyno IL-33 with a K between 10 pM and 40 pM. D It specifically binds to both human and cyno IL-33.

[0401] For example, in some cases, the antibody may have a concentration between about 1 pM and about 1 nM (e.g., between about 1 pM and about 900 pM, between about 1 pM and about 800 pM, between about 1 pM and about 700 pM, between about 1 pM and about 600 pM, between about 1 pM and about 500 pM, between about 1 pM and about 400 pM, between about 1 pM and about 300 pM, between about 1 pM and about 200 pM, between about 1 pM and about 190 pM, between about 1 pM and about 180 pM, between about 1 pM and about 170 pM, between about 1 pM and about 160 pM, between about 1 pM and about 150 pM, between about 1 pM and about 140 pM, between about 1 pM and about 130 pM, between about 1 pM and about 120 pM, between about 1 pM and about 110 pM, between about 1 pM and about 100 pM, between about 1 pM and about 90 pM, between about 1 pM and about 80 pM, between about 1 pM and about 70 pM, between about 1 pM and about 60 pM, between about 1 pM and about 50 pM, between about 1 pM and about 40 pM, between about 1 pM and about 30 pM, between about 1 pM and about 20 pM, or between about 1 pM and about 10 pM) DIn some instances, the antibody specifically binds to human IL-33 at a concentration of between about 1 pM and about 250 nM (e.g., between about 1 pM and about 250 pM, between about 1 pM and about 225 pM, between about 1 pM and about 200 pM, between about 1 pM and about 190 pM, between about 1 pM and about 180 pM, between about 1 pM and about 170 pM, between about 1 pM and about 160 pM, between about 1 pM and about 150 pM, between about 1 pM and about 140 pM, between about 1 pM and about 130 pM, or between about 1 pM and about 160 pM). 0 pM, between about 1 pM and about 120 pM, between about 1 pM and about 110 pM, between about 1 pM and about 100 pM, between about 1 pM and about 90 pM, between about 1 pM and about 80 pM, between about 1 pM and about 70 pM, between about 1 pM and about 60 pM, between about 1 pM and about 50 pM, between about 1 pM and about 40 pM, between about 1 pM and about 30 pM, between about 1 pM and about 20 pM, or between about 1 pM and about 10 pM) D In some instances, the antibody specifically binds to human IL-33 with a K of between about 50 pM and about 180 pM (e.g., between about 50 pM and about 180 pM (e.g., about 50 pM, about 60 pM, about 70 pM, about 80 pM, about 90 pM, about 100 pM, about 110 pM, about 120 pM, about 130 pM, about 140 pM, about 150 pM, about 160 pM, or about 180 pM). D In some instances, the antibody specifically binds to human IL-33 with a K of 118 pM. D In other instances, the antibody specifically binds to human IL-33 with a K of 15 pM. D It specifically binds to human IL-33 at the K D Either of the values ​​can be determined, for example, by surface plasmon resonance, as described herein (see, eg, the Examples, including Examples 4, 6, and 7).

[0402] In some cases, the antibody has a K of about 400 pM or less at 25°C. DFor example, in some instances, the antibody specifically binds to human IL-33 at 25° C. with a K of about 390 pM or less, about 380 pM or less, about 375 pM or less, about 350 pM or less, about 325 pM or less, about 300 pM or less, about 275 pM or less, about 250 pM or less, about 250 pM or less, about 225 pM or less, about 200 pM or less, about 175 pM or less, about 150 pM or less, about 130 pM or less, about 125 pM or less, about 100 pM or less, about 75 pM or less, about 50 pM or less, about 25 pM or less, about 20 pM or less, about 15 pM or less, about 10 pM or less, or about 5 pM or less. D In some instances, the antibody specifically binds to human IL-33 at 25°C with a K of about 1 pM to about 150 pM (e.g., about 1 pM, about 5 pM, about 10 pM, about 15 pM, about 20 pM, about 30 pM, about 40 pM, about 50 pM, about 60 pM, about 70 pM, about 80 pM, about 90 pM, about 100 pM, about 110 pM, about 120 pM, about 130 pM, about 140 pM, or about 150 pM). D In some cases, the antibody specifically binds to human IL-33 with a K of about 15 pM at 25°C. D The antibody specifically binds to human IL-33 at a specific site. The antibody may be a Fab fragment. In some cases, the antibody may be a Fab fragment. D Either of the values ​​can be determined, for example, by surface plasmon resonance, as described herein (see, eg, the Examples, including Examples 4, 6, and 7).

[0403] In some cases, the antibody has a K of about 400 pM or less at 37°C. D For example, in some instances, the antibody specifically binds to human IL-33 at 37° C. with a K of about 390 pM or less, about 380 pM or less, about 375 pM or less, about 350 pM or less, about 325 pM or less, about 300 pM or less, about 275 pM or less, about 250 pM or less, about 250 pM or less, about 225 pM or less, about 200 pM or less, about 175 pM or less, about 150 pM or less, about 130 pM or less, about 125 pM or less, about 100 pM or less, about 75 pM or less, about 50 pM or less, about 25 pM or less, about 20 pM or less, about 15 pM or less, about 10 pM or less, or about 5 pM or less. DIn some instances, the antibody specifically binds to human IL-33 at 37°C with a K of about 1 pM to about 150 pM (e.g., about 1 pM, about 5 pM, about 10 pM, about 15 pM, about 20 pM, about 30 pM, about 40 pM, about 50 pM, about 60 pM, about 70 pM, about 80 pM, about 90 pM, about 100 pM, about 110 pM, about 120 pM, about 130 pM, about 140 pM, or about 150 pM). D In some cases, the antibody specifically binds to human IL-33 with a K of about 15 pM at 37°C. D The antibody specifically binds to human IL-33 at a specific site. The antibody may be a Fab fragment. In some cases, the antibody may be a Fab fragment. D Either of the values ​​can be determined, for example, by surface plasmon resonance, as described herein (see, eg, the Examples, including Examples 4, 6, and 7).

[0404] In some cases, the antibody has a concentration between about 1 pM and about 1 nM (e.g., between about 1 pM and about 900 pM, between about 1 pM and about 800 pM, between about 1 pM and about 700 pM, between about 1 pM and about 600 pM, between about 1 pM and about 500 pM, between about 1 pM and about 400 pM, between about 1 pM and about 300 pM, between about 1 pM and about 200 pM, between about 1 pM and about 190 pM, between about 1 pM and about 180 pM, between about 1 pM and about 170 pM, between about 1 pM and about 160 pM, between about 1 pM and about 1 between about 1 pM and about 150 pM, between about 1 pM and about 140 pM, between about 1 pM and about 130 pM, between about 1 pM and about 120 pM, between about 1 pM and about 110 pM, between about 1 pM and about 100 pM, between about 1 pM and about 90 pM, between about 1 pM and about 80 pM, between about 1 pM and about 70 pM, between about 1 pM and about 60 pM, between about 1 pM and about 50 pM, between about 1 pM and about 40 pM, between about 1 pM and about 30 pM, between about 1 pM and about 20 pM, or between about 1 pM and about 10 pM) DIn some instances, the antibody specifically binds to cytoIL-33 at a concentration of about 100 pM to about 750 pM (e.g., about 100 pM to about 750 pM, about 200 pM to about 750 pM, about 225 pM to about 750 pM, about 250 pM to about 750 pM, about 265 pM to about 750 pM, about 275 pM to about 750 pM, about 300 pM to about 750 pM, about 325 pM to about 750 pM, about 350 pM to about 750 pM, about 375 pM to about 750 pM, or about 385 pM to about 750 pM). Approximately 750pM, approximately 400pM to approximately 750pM, approximately 425pM to approximately 750pM, approximately 450pM to approximately 750pM, approximately 475pM to approximately 750pM, approximately 500pM to approximately 750pM, approximately 525p M~about 750pM, about 550pM to about 750pM, about 575pM to about 750pM, about 600pM to about 750pM, about 650pM to about 750pM, or about 250pM to about 650pM) D In some cases, the aforementioned K D Either of the values ​​can be determined, for example, by surface plasmon resonance, as described herein (see, eg, the Examples, including Examples 4, 6, and 7).

[0405] In some cases, the antibody has a K of about 400 pM or less at 25°C. D For example, in some instances, the antibody specifically binds to cyno IL-33 at 25° C. with a K of about 390 pM or less, about 380 pM or less, about 375 pM or less, about 350 pM or less, about 325 pM or less, about 300 pM or less, about 275 pM or less, about 250 pM or less, about 250 pM or less, about 225 pM or less, about 200 pM or less, about 175 pM or less, about 150 pM or less, about 130 pM or less, about 125 pM or less, about 100 pM or less, about 75 pM or less, about 50 pM or less, about 25 pM or less, about 20 pM or less, about 15 pM or less, about 10 pM or less, or about 5 pM or less. D In some instances, the antibody specifically binds to cyno IL-33 at 25° C. with a K of about 1 pM to about 150 pM (e.g., about 1 pM, about 5 pM, about 10 pM, about 15 pM, about 20 pM, about 30 pM, about 40 pM, about 50 pM, about 60 pM, about 70 pM, about 80 pM, about 90 pM, about 100 pM, about 110 pM, about 120 pM, about 130 pM, about 140 pM, or about 150 pM).D In some cases, the antibody specifically binds to cyno IL-33 at a K of about 22 pM at 25°C. D The antibody specifically binds to cyno IL-33. The antibody may be a Fab fragment. In some cases, the antibody may be a Fab fragment. D Either of the values ​​can be determined, for example, by surface plasmon resonance, as described herein (see, eg, the Examples, including Examples 4, 6, and 7).

[0406] In some cases, the antibody has a K of about 400 pM or less at 37°C. D For example, in some instances, the antibody specifically binds to cyno IL-33 at 37° C. with a K of about 390 pM or less, about 380 pM or less, about 375 pM or less, about 350 pM or less, about 325 pM or less, about 300 pM or less, about 275 pM or less, about 250 pM or less, about 250 pM or less, about 225 pM or less, about 200 pM or less, about 175 pM or less, about 150 pM or less, about 130 pM or less, about 125 pM or less, about 100 pM or less, about 75 pM or less, about 50 pM or less, about 25 pM or less, about 20 pM or less, about 15 pM or less, about 10 pM or less, or about 5 pM or less. D In some instances, the antibody specifically binds to cyno IL-33 at 37°C with a K of about 1 pM to about 150 pM (e.g., about 1 pM, about 5 pM, about 10 pM, about 15 pM, about 20 pM, about 30 pM, about 40 pM, about 50 pM, about 60 pM, about 70 pM, about 80 pM, about 90 pM, about 100 pM, about 110 pM, about 120 pM, about 130 pM, about 140 pM, or about 150 pM). D In some cases, the antibody specifically binds to cyno IL-33 at a K of about 34 pM at 37°C. D The antibody specifically binds to cyno IL-33. The antibody may be a Fab fragment. In some cases, the antibody may be a Fab fragment. D Either of the values ​​can be determined, for example, by surface plasmon resonance, as described herein (see, eg, the Examples, including Examples 4, 6, and 7).

[0407] In some cases, the anti-IL-33 antibodies provided herein can inhibit the binding of IL-33 to an IL-33 receptor. In some cases, inhibition is measured using a cell-based blocking assay. In some cases, the antibodies inhibit the binding of human IL-33 to an IL-33 receptor with a 50% inhibitory concentration (IC50) of between about 750 fM and about 250 pM (e.g., between about 750 fM and about 250 pM, between about 1 pM and about 250 pM, between about 1 pM and about 100 pM, between about 1 pM and about 50 pM, between about 1 pM and about 10 pM, or between about 1 pM and about 5 pM). In some instances, the antibody inhibits the binding of human IL-33 to an IL-33 receptor with an IC50 of about 50 pM or less (e.g., about 50 pM or less, about 40 pM or less, about 30 pM or less, about 20 pM or less, about 15 pM or less, about 10 pM or less, about 9 pM or less, about 8 pM or less, about 7 pM or less, about 6 pM or less, about 5 pM or less, about 4 pM or less, about 3 pM or less, about 2.5 pM or less, about 2 pM or less, about 1 pM or less, about 900 fM or less, about 800 fM or less, or about 750 fM or less). In some instances, the antibody inhibits the binding of human IL-33 to an IL-33 receptor with an IC50 of between about 1 pM and about 50 pM. In some instances, the antibody inhibits the binding of human IL-33 to an IL-33 receptor with an IC50 of about 31 pM. In some cases, inhibition can be achieved by, for example, using HEK-BLUE as described herein. TM It is measured using a cell-based blocking assay using cells (see, for example, the Examples, including Examples 3 and 6).

[0408] In some instances, the antibody inhibits binding of cyno IL-33 to an IL-33 receptor with an IC50 of between about 1 nM and about 10 nM (e.g., between about 1 nM and about 10 nM, between about 1 nM and about 9 nM, between about 1 nM and about 8 nM, between about 1 nM and about 7 nM, between about 1 nM and about 6 nM, between about 1 nM and about 5 nM, between about 1 nM and about 4 nM, or between about 1 nM and about 3 nM). In some instances, the inhibition is observed, for example, in combination with HEK-BLUE IL-33 as described herein. TM It is measured using a cell-based blocking assay using cells (see, for example, the Examples, including Examples 3 and 6).

[0409] Any of the antibodies provided herein may be administered at a concentration of, for example, about 100 mg / mL, about 110 mg / mL, about 120 mg / mL, about 130 mg / mL, about 140 mg / mL, about 150 mg / mL, about 160 mg / mL, about 170 mg / mL, about 180 mg / mL, about 190 mg / mL, about 200 mg / mL, about 210 mg / mL, about 220 mg / mL, about 230 mg / mL, about 240 mg / mL, about 250 mg / mL, 200 mg / mL, about 260 mg / mL, about 270 mg / mL, about 280 mg / mL, about 290 mg / mL, about 300 mg / mL, about 310 mg / mL, about 320 mg / mL, about 330 mg / mL, about 340 mg / mL, about 350 mg / mL, about 360 mg / mL, about 370 mg / mL, about 380 mg / mL, about 390 mg / mL, or about 400 mg / mL, and may have a viscosity of less than about 10 centipoise (cP).

[0410] For example, in some instances, the antibody may be at a concentration of, e.g., about 100 mg / mL, about 110 mg / mL, about 120 mg / mL, about 130 mg / mL, about 140 mg / mL, about 150 mg / mL, about 160 mg / mL, about 170 mg / mL, about 180 mg / mL, about 190 mg / mL, about 200 mg / mL, about 210 mg / mL, about 220 mg / mL, about 230 mg / mL, about 240 mg / mL, about 250 mg / mL, about 260 mg / mL, about 270 mg / mL, about 280 mg / mL, about 290 mg / mL, about 300 mg / mL, about 310 mg / mL, about 320 mg / mL, about 330 mg / mL, about 340 mg / mL, about 350 mg / mL, about 360 mg / mL, about 370 mg / mL, about 380 mg / mL, about 390 mg / mL, about 400 mg / mL, about 410 mg / mL, about 420 mg / mL, about 430 mg / mL, about 440 mg / mL, about 450 mg / mL, about 460 mg / mL, about 470 mg / mL, about 480 mg / mL, about 490 mg / mL, about 500 mg / mL, about 510 mg / mL, about 520 mg / mL, about 530 mg / mL, about 540 mg / mL, about 550 mg / mL, about 560 mg / mL, about 570 mg / mL, about 580 mg / mL, about 590 mg / mL, about 600 mg / mL, about 610 mg / mL, about 620 mg / mL, about 630 mg / mL, about 64 At a concentration of 30 mg / mL, about 340 mg / mL, about 350 mg / mL, about 360 mg / mL, about 370 mg / mL, about 380 mg / mL, about 390 mg / mL, or about 400 mg / mL, it has a viscosity of about 10 cP or less, about 9.5 cP or less, about 9 cP or less, about 8.5 cP or less, about 8 cP or less, about 7.5 cP or less, about 7 cP or less, about 6.5 cP or less, about 6 cP or less, about 5.5 cP or less, about 5 cP or less, about 4.5 cP or less, about 4 cP or less, about 3.5 cP or less, about 3 cP or less, about 2.5 cP or less, about 2 cP or less, about 1.5 cP or less, about 1 cP or less, or about 0.5 cP or less. In some cases, the antibody has a viscosity of about 10 cP or less, about 9.5 cP or less, about 9 cP or less, about 8.5 cP or less, about 8 cP or less, about 7.5 cP or less, about 7 cP or less, about 6.5 cP or less, about 6 cP or less, about 5.5 cP or less, about 5 cP or less, about 4.5 cP or less, about 4 cP or less, about 3.5 cP or less, about 3 cP or less, about 2.5 cP or less, about 2 cP or less, about 1.5 cP or less, about 1 cP, or about 0.5 cP or less, e.g., at a concentration of about 180 mg / mL.

[0411] For example, in some instances, the antibodies provided herein may have a concentration of, e.g., about 100 mg / mL or more (e.g., about 100 mg / mL, about 110 mg / mL, about 120 mg / mL, about 130 mg / mL, about 140 mg / mL, about 150 mg / mL, about 160 mg / mL, about 170 mg / mL, about 180 mg / mL, about 190 mg / mL, about 200 mg / mL, about 210 mg / mL, about 220 mg / mL, about 230 mg / mL, about 240 mg / mL, about 250 mg / mL, about 260 mg / mL, about 270 mg / mL, about 280 mg / mL, about 290 mg / mL, about 300 mg / mL, about 310 mg / mL, about 320 mg / mL, about 330 mg / mL, about 340 mg / mL, about 350 mg / mL, about 360 mg / mL, about 370 mg / mL, about 380 mg / mL, about 390 mg / mL, about 400 mg / mL, about 410 mg / mL, about 420 mg / mL, about 430 mg / mL, about 440 mg / mL, about 450 mg / mL, about 460 mg / mL, about 470 mg / mL, about 480 mg / mL, about 490 mg / mL, about 500 mg / mL, about 510 mg / mL, about 520 mg / mL, about 530 mg / mL, about 540 mg / mL, about 550 mg / mL, about 560 mg / mL, about 570 mg / mL, about 580 mg / mL, about 590 mg / mL, about 600 mg / mL, about 610 mg / mL, about 620 and may have a viscosity of less than about 5 cP at a concentration of about 40 mg / mL, about 250 mg / mL, about 260 mg / mL, about 270 mg / mL, about 280 mg / mL, about 290 mg / mL, about 300 mg / mL, about 310 mg / mL, about 320 mg / mL, about 330 mg / mL, about 340 mg / mL, about 350 mg / mL, about 360 mg / mL, about 370 mg / mL, about 380 mg / mL, about 390 mg / mL, or about 400 mg / mL).In some cases, the antibody may have a concentration of, for example, about 100 mg / mL, about 110 mg / mL, about 120 mg / mL, about 130 mg / mL, about 140 mg / mL, about 150 mg / mL, about 160 mg / mL, about 170 mg / mL, about 180 mg / mL, about 190 mg / mL, about 200 mg / mL, about 210 mg / mL, about 220 mg / mL, about 230 mg / mL, about 240 mg / mL, about 250 mg / mL, about 260 mg / mL, about 270 mg / mL, about 280 mg / mL, about 290 mg / mL, about 300 mg / mL, about 310 mg / mL, about 320 mg / mL, about 330 mg / mL, about 340 mg / mL, about 350 mg / mL, about 360 mg / mL, about 370 mg / mL, about 380 mg / mL, about 390 mg / mL, about 400 mg / mL, about 410 mg / mL, about 420 mg / mL, about 430 mg / mL, about 440 mg / mL, about 450 mg / mL, about 460 mg / mL, about 470 mg / mL, about 480 mg / mL, about 490 mg / mL, about 500 mg / mL, about 510 mg / mL, about 520 mg / mL, about 530 mg / mL, about 540 mg / mL, about 550 mg / mL, about 560 mg / mL, about 570 mg / mL, about 580 mg / mL, about 590 mg / mL, about 600 mg / mL, about 610 mg / mL, about 620 mg / mL, about 630 mg / mL, about 640 mg / mL, about At a concentration of about 330 mg / mL, about 340 mg / mL, about 350 mg / mL, about 360 mg / mL, about 370 mg / mL, about 380 mg / mL, about 390 mg / mL, or about 400 mg / mL, the concentration is between about 0.5 cP and about 5 cP, between about 0.5 cP and about 4.5 cP, between about 0.5 cP and about 4 cP, between about 0.5 cP and about 3.5 cP, between about 0.5 cP and about 3 cP, between about 0.5 cP and about 2.5 cP, between about 0.5 cP and about 2 cP, between about 0.5 cP and about 1.5 cP, between about 0.5 cP and about 1 cP, between about 1 cP and about 5 cP, between about 1 cP and about Between about 1 cP and about 4 cP, between about 1 cP and about 3.5 cP, between about 1 cP and about 3 cP, between about 1 cP and about 2.5 cP, between about 1 cP and about 2 cP, between about 1 cP and about 1.5 cP, between about 1.5 cP and about 5 cP, between about 1.5 cP and about 4.5 cP, between about 1.5 cP and about 4 cP, between about 1.5 cP and about 3.5 cP, between about 1.5 cP and about 3 cP, between about 1.5 cP and about 2.5 cP, between about 1.5 cP and about 2 cP, between about 2 cP and about 5 cP, between about 2 cP and about 4.5 cP, between about 2 cP and about 4 cP, between about 2 cP and about 3.5 cP, The viscosity is between 2 cP and about 3 cP, between about 2 cP and about 2.5 cP, between about 2.5 cP and about 5 cP, between about 2.5 cP and about 4.5 cP, between about 2.5 cP and about 4 cP, between about 2.5 cP and about 3.5 cP, between about 2.5 cP and about 3 cP, between about 3 cP and about 5 cP, between about 3 cP and about 4.5 cP, between about 3 cP and about 4 cP, between about 3 cP and about 3.5 cP, between about 3.5 cP and about 5 cP, between about 3.5 cP and about 4.5 cP, between about 3.5 cP and about 4 cP, between about 4 cP and about 5 cP, between about 4 cP and about 4.5 cP, or between about 4.5 cP and about 5 cP.

[0412] In some cases, the antibody has a saturation of between about 0.5 cP and about 5 cP, between about 0.5 cP and about 4.5 cP, between about 0.5 cP and about 4 cP, between about 0.5 cP and about 3.5 cP, between about 0.5 cP and about 3 cP, between about 0.5 cP and about 2.5 cP, between about 0.5 cP and about 2 cP, between about 0.5 cP and about 1.5 cP, between about 0.5 cP and about 1 cP, or between about Between 1 cP and about 5 cP, between about 1 cP and about 4.5 cP, between about 1 cP and about 4 cP, between about 1 cP and about 3.5 cP, between about 1 cP and about 3 cP, between about 1 cP and about 2.5 cP, between about 1 cP and about 2 cP, between about 1 cP and about 1.5 cP, between about 1.5 cP and about 5 cP, between about 1.5 cP and about 4.5 cP, between about 1.5 cP and about 4 cP, between about 1.5 cP and about 3.5 cP, about 1.5 cP Between about 1.5cP and about 3cP, between about 1.5cP and about 2.5cP, between about 1.5cP and about 2cP, between about 2cP and about 5cP, between about 2cP and about 4.5cP, between about 2cP and about 4cP, between about 2cP and about 3.5cP, between about 2cP and about 3cP, between about 2cP and about 2.5cP, between about 2.5cP and about 5cP, between about 2.5cP and about 4.5cP, between about 2.5cP and about 4cP, between about 2.5cP and The viscosity is between about 3.5 cP, between about 2.5 cP and about 3 cP, between about 3 cP and about 5 cP, between about 3 cP and about 4.5 cP, between about 3 cP and about 4 cP, between about 3 cP and about 3.5 cP, between about 3.5 cP and about 5 cP, between about 3.5 cP and about 4.5 cP, between about 3.5 cP and about 4 cP, between about 4 cP and about 5 cP, between about 4 cP and about 4.5 cP, or between about 4.5 cP and about 5 cP.

[0413] In certain cases, the antibody may have a viscosity of about 4.6 cP at a concentration of about 180 mg / mL.

[0414] Any of the antibodies provided herein can be, for example, at a concentration of about 100 mg / mL or more (e.g., about 100 mg / mL or more, about 110 mg / mL or more, about 120 mg / mL or more, about 130 mg / mL or more, about 140 mg / mL or more, about 140 mg / mL or more, about 150 mg / mL or more, about 160 mg / mL or more, about 170 mg / mL or more, about 180 mg / mL or more, about 190 mg / mL or more, about 200 mg / mL or more, about 210 mg / mL or more, about 220 mg / mL or more), e.g., in any suitable buffer (e.g., phosphate buffered saline (PBS) pH 7.4). and / or a concentration of about 230 mg / mL or more, about 240 mg / mL or more, about 250 mg / mL or more, about 260 mg / mL or more, about 270 mg / mL or more, about 280 mg / mL or more, about 290 mg / mL or more, about 300 mg / mL or more, about 310 mg / mL or more, about 320 mg / mL or more, about 330 mg / mL or more, about 340 mg / mL or more, about 350 mg / mL or more, about 360 mg / mL or more, about 370 mg / mL or more, about 380 mg / mL or more, about 390 mg / mL or more, or about 400 mg / mL or more.For example, any of the antibodies provided herein may be present in, for example, any suitable buffer (e.g., phosphate buffered saline (PBS) pH 7.4) at a concentration of, for example, about 100 mg / mL or more (e.g., about 100 mg / mL or more, about 110 mg / mL or more, about 120 mg / mL or more, about 130 mg / mL or more, about 140 mg / mL or more, about 140 mg / mL or more, about 150 mg / mL or more, about 160 mg / mL or more, about 170 mg / mL or more, about 180 mg / mL or more, about 190 mg / mL or more, about 200 mg / mL or more, about 210 mg / mL or more, about 220 mg / mL or more, about 230 mg / mL or more, about 240 mg / mL or more, about 250 mg / mL or more). and a turbidity (optical density (OD)) of about 0.5 or less, about 0.45 or less, about 0.4 or less, about 0.35 or less, about 0.3 or less, about 0.25 or less, about 0.2 or less, about 0.15 or less, about 0.1 or less, or about 0.05 or less at a concentration of about 260 mg / mL or more, about 270 mg / mL or more, about 280 mg / mL or more, about 290 mg / mL or more, about 300 mg / mL or more, about 310 mg / mL or more, about 320 mg / mL or more, about 330 mg / mL or more, about 340 mg / mL or more, about 350 mg / mL or more, about 360 mg / mL or more, about 370 mg / mL or more, about 380 mg / mL or more, about 390 mg / mL or more, or about 400 mg / mL or more.

[0415] In some cases, any of the antibodies provided herein may be present in a concentration of, for example, about 100 mg / mL or more (e.g., about 100 mg / mL or more, about 110 mg / mL or more, about 120 mg / mL or more, about 130 mg / mL or more, about 140 mg / mL or more, about 150 mg / mL or more, about 160 mg / mL or more, about 170 mg / mL or more, about 180 mg / mL or more, about 190 mg / mL or more, about 200 mg / mL or more, about 210 mg / mL or more, about 220 mg / mL or more, about 230 mg / mL or more, about 240 mg / mL or more, about 250 mg / mL or more, about 260 mg / mL or more, about 270 mg / mL or more, about 280 mg / mL or more, about 290 mg / mL or more, about 300 mg / mL or more, about 310 mg / mL or more, about 320 mg / mL or more, about 330 mg / mL or more, about 340 mg / mL or more, about 350 mg / mL or more, about 360 mg / mL or more, about 370 mg / mL or more, about 380 mg / mL or more, about 390 mg / mL or more, about 400 mg / mL or more, about 410 mg / mL or more, about 420 mg / mL or more, about 430 mg / mL or more, about 440 mg / mL or more, about 450 mg / mL or more, about 460 mg / mL or more, about 470 mg / mL or more, about 480 mg / mL or more, about 490 mg / mL or more, about 500 mg / mL or more, about 510 mg / mL or more, about 520 mg / mL or more, about At a concentration of 20 mg / mL or more, about 230 mg / mL or more, about 240 mg / mL or more, about 250 mg / mL or more, about 260 mg / mL or more, about 270 mg / mL or more, about 280 mg / mL or more, about 290 mg / mL or more, about 300 mg / mL or more, about 310 mg / mL or more, about 320 mg / mL or more, about 330 mg / mL or more, about 340 mg / mL or more, about 350 mg / mL or more, about 360 mg / mL or more, about 370 mg / mL or more, about 380 mg / mL or more, about 390 mg / mL or more, or about 400 mg / mL or more, between about 0.5, between about 0.15 and about 0.5, between about 0.2 and about 0.5, between about 0.25 and about 0.5, between about 0.3 and about 0.5, between about 0.35 and about 0.5, between about 0.4 and about 0.5, between about 0.45 and about 0.5, between about 0.05 and about 0.45, between about 0.1 and about 0.45, between about 0.15 and about 0.45, between about 0.2 and about 0.45, between about 0.25 and about 0.45, between about 0.3 and about 0.45, between about 0.35 and about 0.45, between about 0.4 and about 0.45, between about 0.05 and about 0.4, between about 0.1 and about 0.4, between about 0.15 and about 0.4, Between about 0.4, between about 0.25 and about 0.4, between about 0.3 and about 0.4, between about 0.35 and about 0.4, between about 0.05 and about 0.35, between about 0.1 and about 0.35, between about 0.15 and about 0.35, between about 0.2 and about 0.35, between about 0.25 and about 0.35, between about 0.3 and about 0.35, between about 0.05 and about 0.3, between about 0.1 and about 0.3, between about 0.15 and about 0.3, between about 0.2 and about 0.3, between about 0.25 and about 0.3, between about 0.05 and about 0.25, between about 0.1 and about 0.25, between about 0.15 and about 0.25, between about 0.2 and about 0.25, between about 0.05 and about 0.The turbidity (OD) may be between about 0.2, between about 0.1 and about 0.2, between about 0.1 and about 0.2, between about 0.15 and about 0.2, between about 0.05 and about 0.15, between about 0.1 and about 0.15, or between about 0.05 and about 0.1.

[0416] In some cases, any of the antibodies provided herein may be administered at a concentration of, for example, about 150 mg / mL or greater, in any suitable buffer (e.g., phosphate buffered saline (PBS) pH 7.4), at a concentration of between about 0.05 and about 0.5, between about 0.1 and about 0.5, between about 0.15 and about 0.5, between about 0.2 and about 0.5, between about 0.25 and about 0.5, between about 0.3 and about 0.5, between about 0.35 and about 0.5, between about 0.45 and about 0.45, between about 0.50 and about 0.50, between about 0.55 and about 0.50 ... Between about 0.5, between about 0.4 and about 0.5, between about 0.45 and about 0.5, between about 0.05 and about 0.45, between about 0.1 and about 0.45, between about 0.15 and about 0.45, between about 0.2 and about 0.45, between about 0.25 and about 0.45, between about 0.3 and about 0.45, between about 0.35 and about 0.45, between about 0.4 and about 0.45, between about 0.05 and about 0.4, between about 0.1 and about 0.4, between about 0.15 and about 0 Between about 0.4, between about 0.2 and about 0.4, between about 0.25 and about 0.4, between about 0.3 and about 0.4, between about 0.35 and about 0.4, between about 0.05 and about 0.35, between about 0.1 and about 0.35, between about 0.15 and about 0.35, between about 0.2 and about 0.35, between about 0.25 and about 0.35, between about 0.3 and about 0.35, between about 0.05 and about 0.3, between about 0.1 and about 0.3, between about 0.15 and about 0.3 The turbidity (OD) may be between about 0.2 and about 0.3, between about 0.25 and about 0.3, between about 0.05 and about 0.25, between about 0.1 and about 0.25, between about 0.15 and about 0.25, between about 0.2 and about 0.25, between about 0.05 and about 0.2, between about 0.1 and about 0.2, between about 0.15 and about 0.2, between about 0.05 and about 0.15, between about 0.1 and about 0.15, or between about 0.05 and about 0.1.

[0417] In some cases, any of the antibodies provided herein may have a turbidity (OD) of between about 0.25 and about 0.5 at a concentration of about 150 mg / mL to about 250 mg / mL.

[0418] In certain instances, the antibody has a turbidity (OD) of about 0.38 at a concentration of about 200 mg / ml.

[0419] In some cases, any of the anti-IL-33 antibodies described herein (e.g., described above or below) may have one or more (e.g., one, two, three, four, or five) of the following characteristics: (i) the antibody has a K of between about 1 pM and about 200 pM. D (ii) the antibody specifically binds to human IL-33 at a K between about 1 pM and about 200 pM; D (iii) the antibody specifically binds to cyno IL-33, e.g., HEK-BLUE TM In a cell-based blocking assay using cells, the antibody inhibits the binding of human IL-33 to an IL-33 receptor (e.g., ST2 and / or IL-1RAcP) with an IC50 of between about 1 pM and about 250 pM, (iv) the antibody has a viscosity of between about 3 cP and about 5 cP at a concentration of about 180 mg / mL; and / or (v) the antibody has a turbidity (OD) of between about 0.25 and about 0.5 at a concentration of about 150 mg / mL and about 250 mg / mL. In some cases, any of the anti-IL-33 antibodies described herein may have one of the aforementioned characteristics. In some cases, any of the anti-IL-33 antibodies described herein may have two of the aforementioned characteristics. In some cases, any of the anti-IL-33 antibodies described herein may have three of the aforementioned characteristics. In some cases, any of the anti-IL-33 antibodies described herein may have four of the aforementioned characteristics. In some cases, any of the anti-IL-33 antibodies described herein may have all five of the aforementioned characteristics.

[0420] Any of the anti-IL-33 antibodies provided herein can be a monoclonal antibody, including a chimeric, humanized, or human antibody.

[0421] Any of the anti-IL-33 antibodies provided herein may be an antibody fragment, such as an Fv, Fab, Fab', scFv, diabody, or F(ab')2 fragment. In certain cases, the antibody fragment is a Fab fragment.

[0422] In other cases, any of the anti-IL-33 antibodies provided herein can be a full-length antibody, such as an intact IgG1 antibody, an intact IgG4 antibody, or another antibody class or isotype as defined herein. In some cases, the antibody is an IgG4 antibody comprising a mutation in the hinge region. In some cases, the mutation is a substitution mutation. In some cases, the substitution mutation is at amino acid residue S228 (EU numbering). In some cases, the substitution mutation is an S228P mutation.

[0423] Any of the anti-IL-33 antibodies provided herein can be monospecific antibodies. In other cases, any of the anti-IL-33 antibodies provided herein can be multispecific antibodies (e.g., bispecific antibodies). In some cases, the bispecific antibody comprises a second binding domain that binds to a second biological molecule, where the second biological molecule is interleukin-13 (IL-13), interleukin-4 (IL-4), interleukin-5 (IL-5), interleukin-17 (IL-17), factor D, HtrA1, VEGF, or a VEGF receptor.

[0424] In further aspects, any of the anti-IL-33 antibodies disclosed herein can incorporate any of the features described in Sections 1-7 below, either alone or in combination:

[0425] 1: Antibody affinity In certain embodiments, the antibodies provided herein have a cytotoxicity of ≦1 μM, ≦100 nM, ≦10 nM, ≦1 nM, ≦0.1 nM, ≦0.01 nM, ≦1 pM, or ≦0.1 pM (e.g., 10 -6 M or less, e.g., 10 -6 M~10 -9 M or less, e.g. 10 -9 M~10 -13 Dissociation constant (K D )

[0426] In one embodiment, K Dis measured by a radiolabeled antigen binding assay (RIA). In one embodiment, an RIA is performed using a Fab version of the antibody of interest and its antigen. For example, the solution binding affinity of a Fab for an antigen is measured by measuring the binding affinity of the Fab to the antigen in the presence of a titration series of unlabeled antigen at a minimum concentration of ( 125 I) Fab is equilibrated with labeled antigen, and then bound antigen is measured by capturing it on a plate coated with an anti-Fab antibody (see, e.g., Chen et al. J. Mol. Biol. 293:865-881, 1999). To establish the conditions for the assay, MICROTITER® multiwell plates (Thermo Scientific) are coated overnight with 5 μg / mL of capturing anti-Fab antibody (Cappel Labs) in 50 mM carbonate (pH 9.6), followed by blocking with 2% (w / v) bovine serum albumin in PBS for 2-5 hours at room temperature (approximately 23°C). Non-adsorbent plates (NUNC TM #269620) at 100 pM or 26 pM [ 125 The [I]-antigen is mixed with serial dilutions of the Fab of interest (e.g., consistent with the evaluation of anti-VEGF antibody Fab-12 in Presta et al., Cancer Res. 57:4593-4599 (1997)). The Fab of interest is then incubated overnight. However, incubation may be continued for a longer period (e.g., about 65 hours) to ensure equilibrium is reached. The mixture is then transferred to a capture plate and incubated at room temperature (e.g., 1 hour). The solution is then removed, and the plate is washed eight times with 0.1% polysorbate 20 (TWEEN®-20) in PBS. When the plate has dried, 150 μL / well of scintillant (MICROSCINT-20) is added. TM Packard) was added and the plate was incubated for 10 minutes in TOPCOUNT TM Count in a gamma counter (Packard). Concentrations of each Fab that yield 20% or less of maximal binding are selected for use in competitive binding assays.

[0427] According to another embodiment, K Dis measured using a BIACORE® surface plasmon resonance assay. For example, assays using a BIACORE®-2000 or BIACORE®-3000 (BIAcore, Inc.) are performed at 25°C using an immobilized antigen CM5 chip with approximately 10 response units (RU). In one embodiment, a carboxymethylated dextran biosensor chip (CM5, BIACORE) is activated with N-ethyl-N'-(3-dimethylaminopropyl)carbodiimide hydrochloride (EDC) and N-hydroxysuccinimide (NHS) according to instructions in the art. The antigen is diluted in 10 mM sodium acetate, pH 4.8, to 5 μg / mL (approximately 0.2 μM) before injection at a flow rate of 5 μL / min to achieve approximately 10 response units (RU) of bound protein. After antigen injection, 1 M ethanolamine is injected to block unreacted groups. For kinetic measurements, two-fold serial dilutions of Fab (0.78 nM to 500 nM) are injected into phosphate-buffered saline (PBS) containing 0.05% polysorbate 20 (TWEEN®-20) surfactant (PBST) at a flow rate of approximately 25 μL / min at 25°C. The association rate (k on ) and dissociation rate (k off The equilibrium dissociation constant (K) is calculated by simultaneously fitting the association and dissociation sensorgrams using a simple one-to-one Langmuir binding model (BIACORE® Evaluation Software version 3.2). D ) is k off / k on The ratio is calculated as a ratio. See, for example, Chen et al. (J. Mol. Biol. 293:865-881, 1999). When the association rate by the surface plasmon resonance assay described above is 10 6 M -1 s -1above, the association rate can be determined using a fluorescence quenching technique measuring the increase or decrease in fluorescence emission intensity (excitation = 295 nm, emission = 340 nm, 16 nm bandpass) of 20 nM anti-antigen antibody (Fab form) in PBS (pH 7.2) at 25°C in the presence of increasing antigen concentrations as measured in a spectrometer such as a spectrophotometer equipped with stopped flow (Aviv Instruments) or an 8000 Series SLM-AMINCO™ spectrophotometer (ThermoSpectronic) with a stirred cuvette.

[0428] 2: Antibody fragment Any of the antibodies provided herein may be an antibody fragment (e.g., an antigen-binding (e.g., IL-33-binding) antibody fragment). Antibody fragments include, but are not limited to, Fab, Fab', Fab'-SH, F(ab')2, Fv, and scFv fragments, as well as other fragments described below. In certain cases, the antibody fragment is a Fab. For a review of certain antibody fragments, see Hudson et al. Nat. Med. 9:129-134 (2003). For a review of scFv fragments, see, e.g., Pluckthuen, The Pharmacology of Monoclonal Antibodies, vol. 113, Rosenburg and Moore eds., (Springer-Verlag, New York), pp. 269-315 (1994). See also WO 93 / 16185 and U.S. Pat. Nos. 5,571,894 and 5,587,458. See US Pat. No. 5,869,046 for a discussion of Fab and F(ab')2 fragments that contain salvage receptor binding epitope residues and have increased in vivo half-lives.

[0429] Diabodies are antibody fragments with two antigen-binding sites that can be bivalent or bispecific. See, e.g., European Patent Application Publication No. 404,097, International Publication No. 1993 / 01161, Hudson et al., Nat. Med. 9:129-134, 2003; and Hollinger et al., Proc. Natl. Acad. Sci. USA 90, 6444-6448, 1993. Triabodies and tetrabodies are also described in Hudson et al., Nat. Med. 9:129-134, 2003.

[0430] Single domain antibodies are antibody fragments that contain all or part of the heavy chain variable domain or all or part of the light chain variable domain of an antibody. In certain embodiments, single domain antibodies are human single domain antibodies (see, e.g., U.S. Pat. No. 6,248,516 B1).

[0431] Antibody fragments can be produced by a variety of techniques, including, but not limited to, proteolytic digestion of intact antibodies and production by recombinant host cells (e.g., E. coli or phage), as described herein.

[0432] 3: Chimeric and humanized antibodies In certain embodiments, the antibodies provided herein are chimeric antibodies. Certain chimeric antibodies are described, for example, in U.S. Patent No. 4,816,567; and Morrison et al. Proc. Natl. Acad. Sci. USA, 81:6851-6855, 1984). In one example, a chimeric antibody comprises a non-human variable region (e.g., a variable region derived from a mouse, rat, hamster, rabbit, or non-human primate, e.g., a monkey) and a human constant region. In a further example, a chimeric antibody is a "class-switched" antibody, in which the class or subclass has been changed from that of the parent antibody. Chimeric antibodies include antigen-binding fragments thereof. In certain embodiments, a chimeric antibody is a humanized antibody. Typically, a non-human antibody is humanized to reduce immunogenicity to humans while retaining the specificity and affinity of the parent non-human antibody. Generally, a humanized antibody comprises one or more variable domains, the HVRs (or portions thereof) of which are derived from a non-human antibody, and the FRs (or portions thereof) of which are derived from human antibody sequences. A humanized antibody also optionally comprises at least a portion of a human constant region. In some embodiments, some FR residues in the humanized antibody are substituted with corresponding residues from the non-human antibody (e.g., the antibody from which the HVR residues were derived), e.g., to restore or improve antibody specificity or affinity.

[0433] Humanized antibodies and methods for their production are reviewed, for example, in Almagro et al. Front. Biosci. 13:1619-1633, 2008, and further described, for example, in Riechmann et al. Nature 332:323-329, 1988; Queen et al. Proc. Natl. Acad. Sci. USA 86:10029-10033, 1989; U.S. Patent Nos. 5,821,337, 7,527,791, 6,982,321, and 7,087,409; Kashmiri et al. Methods 36:25-34, 2005 (describing specificity-determining region (SDR) grafting); Padlan, Mol. Immunol. 28:489-498, 1991 (describing resurfacing); Dall'Acqua et al. Methods 36:43-60, 2005 (describing "FR shuffling"); and Osbourn et al. Methods 36:61-68, 2005 and Klimka et al. Br. J. Cancer, 83:252-260, 2000 (describing a "guided selection" approach to FR shuffling).

[0434] Human framework regions that can be used for humanization include, but are not limited to, framework regions selected using the "best-fit" method (see, e.g., Sims et al. J. Immunol. 151:2296, 1993); framework regions derived from consensus sequences of human antibodies of particular subgroups of light or heavy chain variable regions (see, e.g., Carter et al. Proc. Natl. Acad. Sci. USA, 89:4285, 1992; and Presta et al. J. Immunol., 151:2623, 1993); human mature (somatically mutated) framework regions or human germline framework regions (see, e.g., Almagro et al. Front. Biosci. 13:1619-1633, 2008); and framework regions derived from screening of FR libraries (see, e.g., Baca et al. J. Biol. Chem. 272:10678-10684, 1997; and Rosok et al. al. J. Biol. Chem. 271:22611-22618, 1996).

[0435] 4: Human antibodies In certain embodiments, the antibodies provided herein are human antibodies. Human antibodies can be produced using various techniques known in the art. Human antibodies are generally described in van Dijk et al. Curr. Opin. Pharmacol. 5:368-74, 2001 and Lonberg, Curr. Opin. Immunol. 20:450-459, 2008.

[0436] Human antibodies may be prepared by administering immunogens to transgenic animals that have been engineered to produce intact human antibodies or intact antibodies with human variable regions in response to antigen challenge. Such animals typically contain all or part of human immunoglobulin loci that replace endogenous immunoglobulin loci or that are present extrachromosomally or randomly integrated into the animal's chromosomes. In such transgenic mice, endogenous immunoglobulin loci are generally inactivated. For a review of methods for obtaining human antibodies from transgenic animals, see Lonberg, Nat. Biotech. 23:1117-1125, 2005. See also, for example, XENOMOUSE. TM See also U.S. Patent Nos. 6,075,181 and 6,150,584, which describe HUMAB® technology; U.S. Patent No. 5,770,429, which describes HUMAB® technology; U.S. Patent No. 7,041,870, which describes KM MOUSE® technology; and U.S. Patent Application Publication No. 2007 / 0061900, which describes VELOCIMOUSE® technology. The human variable regions from intact antibodies produced by such animals can be further modified, for example, by combining them with different human constant regions.

[0437] Human antibodies can also be produced by hybridoma-based methods. Human myeloma and mouse-human heteromyeloma cell lines for producing human monoclonal antibodies have been described. (See, e.g., Kozbor J. Immunol. 133:3001, 1984; Brodeur et al. Monoclonal Antibody Production Techniques and Applications, pp. 51-63 (Marcel Dekker, Inc., New York, 1987); and Boerner et al. J. Immunol. 147:86, 199.) Human antibodies generated via human B cell hybridoma technology are also described by Li et al. Proc. Natl. Acad. Sci. USA, 103:3557-3562, 2006. Further methods include, for example, U.S. Patent No. 7,189,826 (which describes the production of monoclonal human IgM antibodies from hybridoma cell lines) and Ni, Xiandai Mianyixue, 26(4):265-268, 2006 (which describes human-human hybridomas). Human hybridoma technology (trioma technology) is also described in Vollmers et al., Histology and Histopathology 20(3):927-937, 2005 and Vollmers et al., Methods and Findings in Experimental and Clinical Pharmacology 27(3):185-91, 2005.

[0438] Human antibodies can also be produced by isolating Fv clone variable domain sequences selected from human-derived phage display libraries. These variable domain sequences can then be combined with desired human constant domains. Techniques for selecting human antibodies from antibody libraries are described below.

[0439] 5: Library-derived antibodies Antibodies of the invention can be isolated by screening combinatorial libraries for antibodies with one or more desired activities. For example, various methods are known in the art for generating phage display libraries and screening such libraries for antibodies with desired binding characteristics. Such methods are reviewed, for example, by Hoogenboom et al. in Methods in Molecular Biology 178:1-37 (O'Brien et al., ed., Human Press, Totowa, NJ, 2001), and are also described in, for example, McCafferty et al. Nature 348:552-554, 1990; Clackson et al. Nature 352:624-628, 1991; Marks et al. J. Mol. Biol. 222:581-597, 1992; Marks et al., Methods in Molecular Biology 248:161-175 (Lo, ed., Human Press, Totowa, NJ, 2003); Sidhu et al. J. Mol. Biol. 338(2):299-310, 2004; Lee et al. al. J. Mol. Biol. 340(5):1073-1093, 2004; Fellouse, Proc. Natl. Acad. Sci. USA 101(34):12467-12472, 2004; and Lee et al. J. Immunol. Methods 284(1-2):119-132, 2004.

[0440] In one particular phage display method, repertoires of VH and VL genes are cloned separately by polymerase chain reaction (PCR) and randomly recombined in phage libraries, followed by screening for antigen-binding phage as described by Winter et al. Ann. Rev. Immunol., 12:433-455, 1994. Phages typically display antibody fragments, either as single-chain Fv (scFv) fragments or as Fab fragments. Libraries from immune sources provide high-affinity antibodies against the immunogen without the need for hybridoma construction. Alternatively, naive repertoires can be cloned (e.g., from humans) without immunization to provide a single source of antibodies against a wide range of non-self and also self antigens, as described by Griffiths et al., EMBO J, 12:725-734 (1993). Finally, naive libraries can also be generated synthetically by cloning unrearranged V gene segments from stem cells and using PCR primers containing random sequences to encode the highly variable HVR3 region, and achieving rearrangement in vitro as described by Hoogenboom et al. J. Mol. Biol., 227:381-388, 1992. Patent publications describing human antibody phage libraries include, for example: U.S. Pat. No. 5,750,373, and U.S. Patent Application Publication Nos. 2005 / 0079574, 2005 / 0119455, 2005 / 0266000, 2007 / 0117126, 2007 / 0160598, 2007 / 0237764, 2007 / 0292936, and 2009 / 0002360.

[0441] Antibodies or antibody fragments isolated from a human antibody library are considered human antibodies or human antibody fragments herein.

[0442] 6:4. Multispecific antibodies In certain embodiments, the antibodies provided herein are multispecific antibodies, e.g., bispecific antibodies. Multispecific antibodies are monoclonal antibodies that have binding specificities for at least two different sites. In certain embodiments, bispecific antibodies can bind to two different epitopes of IL-33. In certain embodiments, one of the binding specificities is for IL-33 and the other is for any other antigen (e.g., a second biological molecule, such as IL-13, IL-4, IL-5, IL-17, Factor D, HtrA1, VEGF, or a VEGF receptor). Thus, a bispecific antibody may have binding specificity for IL-33 and IL-13; IL-33 and IL-4; IL-33 and IL-5; IL-33 and IL-17; IL-33 and Factor D; IL-33 and HtrA1; IL-33 and VEGF; or IL-33 and a VEGF receptor (e.g., VEGFR1, VEGFR2, VEGFR3, membrane-bound VEGF receptor (mbVEGFR), or soluble VEGF receptor (sVEGFR)). In some cases, a bispecific antibody may have binding specificity for IL-33 and Factor D. In some cases, a bispecific antibody may have binding specificity for IL-33 and HtrA1. In still other cases, a bispecific antibody may have binding specificity for IL-33 and VEGF. In other cases, a bispecific antibody may have binding specificity for IL-33 and a VEGF receptor. In particular, a bispecific antibody may have binding specificity for IL-33 and IL-13. Bispecific antibodies can be prepared as full-length antibodies or antibody fragments.

[0443] Techniques for generating multispecific antibodies include, but are not limited to, recombinant co-expression of two immunoglobulin heavy chain-light chain pairs with different specificities (see Milstein et al. Nature 305:537, 1983; WO 93 / 08829, and Traunecker et al. EMBO J. 10:3655, 1991), and "knob-in-hole" engineering (see, e.g., U.S. Pat. No. 5,731,168). Multispecific antibodies can also be produced by various techniques, such as the manipulation of electrostatic steering effects to create antibody Fc heterodimeric molecules (WO 2009 / 089004 A1); cross-linking of two or more antibodies or fragments (see, e.g., U.S. Pat. No. 4,676,980, and Brennan et al. Science, 229:81, 1985); the use of leucine zippers to create bispecific antibodies (see, e.g., Kostelny et al. J. Immunol., 148(5):1547-1553, 1992); the use of "diabody" technology to create bispecific antibody fragments (see, e.g., Hollinger et al. Proc. Natl. Acad. Sci. USA 90:6444-6448, 1993); and the use of single-chain Fv (sFv) dimers (see, e.g., Gruber et al. al. J. Immunol. 152:5368, 1994); and for example, by the preparation of trispecific antibodies as described in Tutt et al. J. Immunol. 147:60, 1991.

[0444] Engineered antibodies with three or more functional antigen binding sites, including "octopus antibodies," are also included herein (see, e.g., U.S. Patent Application Publication No. 2006 / 0025576 A1).

[0445] The antibodies or fragments herein also include "dual acting Fabs" or "DAFs" that contain antigen binding sites that bind to IL-33 and another distinct antigen (see, e.g., U.S. Patent Application Publication No. 2008 / 0069820).

[0446] Knob-into-Hole The use of knobs-into-holes as a method for producing multispecific antibodies is described, for example, in U.S. Pat. No. 5,731,168, WO 2009 / 089004, U.S. Patent Application Publication No. 2009 / 0182127, U.S. Patent Application Publication No. 2011 / 0287009, Marvin and Zhu, Acta Pharmacol. Sin. (2005) 26(6):649-658, and Kontermann (2005) Acta Pharmacol. Sin., 26:1-9. A brief, non-limiting discussion is provided below.

[0447] A "protuberance" refers to at least one amino acid side chain that protrudes from the interface of a first polypeptide and is therefore capable of positioning within a complementary cavity in an adjacent interface (i.e., the interface of a second polypeptide), thereby stabilizing heteromultimers and thereby favoring heteromultimer formation over homomultimer formation. The protuberance can be present in the original interface or can be introduced synthetically (e.g., by modifying the nucleic acid encoding the interface). In some embodiments, the nucleic acid encoding the interface of the first polypeptide is modified to encode the protuberance. To achieve this, nucleic acid encoding at least one "original" amino acid residue in the interface of the first polypeptide is replaced with nucleic acid encoding at least one "import" amino acid residue having a side chain volume larger than that of the original amino acid residue. It will be understood that there can be more than one original residue and corresponding import residue. The side chain volumes of various amino residues are shown, for example, in Table 1 of US Patent Application Publication No. 2011 / 0287009 or Table 1 of US Pat. No. 7,642,228.

[0448] In some embodiments, the import residue for formation of the bulge is a naturally occurring amino acid residue selected from arginine (R), phenylalanine (F), tyrosine (Y), and tryptophan (W). In some embodiments, the import residue is tryptophan or tyrosine. In some embodiments, the original residue for formation of the bulge has a small side chain volume, such as alanine, asparagine, aspartic acid, glycine, serine, threonine, or valine. See, e.g., U.S. Patent No. 7,642,228.

[0449] A "cavity" refers to at least one amino acid side chain that is recessed from the interface of a second polypeptide and thus accommodates a corresponding protuberance on the adjacent interface of a first polypeptide. The cavity can be present in the original interface or can be introduced synthetically (e.g., by modifying the nucleic acid encoding the interface). In some embodiments, the nucleic acid encoding the interface of the second polypeptide is modified to encode the cavity. To accomplish this, the nucleic acid encoding at least one "original" amino acid residue in the interface of the second polypeptide is replaced with DNA encoding at least one "import" amino acid residue having a smaller side chain volume than the original amino acid residue. It will be understood that there can be more than one original residue and corresponding import residue. In some embodiments, the import residue for forming the cavity is a naturally occurring amino acid residue selected from alanine (A), serine (S), threonine (T), and valine (V). In some embodiments, the import residue is serine, alanine, or threonine. In some embodiments, the original residue for cavity formation has a large side chain volume, such as tyrosine, arginine, phenylalanine, or tryptophan.

[0450] The protuberance is "positionable" within the cavity, meaning that the spatial location of the protuberance and cavity at the interface between the first and second polypeptides, and the size of the protuberance and cavity, respectively, are such that the protuberance can be positioned within the cavity without significantly disrupting the normal association of the first and second polypeptides at the interface. Protuberances such as Tyr, Phe, and Trp typically do not extend perpendicular to the axis of the interface and do not have preferred conformations, and alignment of the protuberance with the corresponding cavity may, in some cases, rely on modeling the protuberance / cavity pair based on three-dimensional structures, such as those obtained by X-ray crystallography or nuclear magnetic resonance (NMR). This can be achieved using techniques widely accepted in the art.

[0451] In some embodiments, the knob mutation in the IgG1 constant region is T366W. In some embodiments, the hole mutation in the IgG1 constant region comprises one or more mutations selected from T366S, L368A, and Y407V. In some embodiments, the hole mutation in the IgG1 constant region comprises T366S, L368A, and Y407V.

[0452] In some embodiments, the knob mutation in the IgG4 constant region is T366W. In some embodiments, the hole mutation in the IgG4 constant region comprises one or more mutations selected from T366S, L368A, and Y407V. In some embodiments, the hole mutation in the IgG4 constant region comprises T366S, L368A, and Y407V.

[0453] 7: Antibody variants In certain embodiments, amino acid sequence variants of the antibodies provided herein are contemplated. For example, it may be desirable to improve the binding affinity and / or other biological properties of the antibody. Amino acid sequence variants of antibodies may be prepared by introducing appropriate modifications into the nucleotide sequence encoding the antibody, or by peptide synthesis. Such modifications include, for example, deletions from, and / or insertions into, and / or substitutions of, residues within the amino acid sequence of the antibody. Any combination of deletion, insertion, and substitution can be made to arrive at the final construct, provided that the final construct possesses the desired properties, e.g., antigen binding.

[0454] a) Substitution, insertion, and deletion variants In certain embodiments, antibody variants with one or more amino acid substitutions are provided. Sites of interest for substitutional mutagenesis include HVRs and FRs. Conservative substitutions are shown in Table A under the heading of "Preferred Substitutions." More substantial changes are shown in Table A under the heading of "Exemplary Substitutions" and are further described below with reference to amino acid side chain classes. Amino acid substitutions can be introduced into the antibody of interest and the products screened for the desired activity, e.g., retained / improved antigen binding, reduced immunogenicity, or improved ADCC or CDC. TIFF2026031968000002.tif168170

[0455] Amino acids can be grouped according to common side chain properties. (1) Hydrophobic: Norleucine, Met, Ala, Val, Leu, Ile; (2) Neutral hydrophilic: Cys, Ser, Thr, Asn, Gln; (3) Acidic: Asp, Glu; (4) basic: His, Lys, Arg; (5) Residues affecting chain orientation: Gly, Pro; (6) Aromatic: Trp, Tyr, Phe.

[0456] Non-conservative substitutions would involve exchanging a member of one of these classes for another class.

[0457] One type of substitutional variant involves substituting one or more HVR (e.g., CDR) residues of a parent antibody (e.g., a humanized or human antibody). Generally, the resulting variant(s) selected for further study will have altered (e.g., improved) certain biological properties (e.g., increased affinity, reduced immunogenicity) compared to the parent antibody and / or will substantially retain certain biological properties of the parent antibody. An exemplary substitutional variant is an affinity-matured antibody, which can be conveniently generated using, for example, phage-display-based affinity maturation techniques such as those described herein. Briefly, one or more HVR residues are mutated and the variant antibodies are displayed on phage and screened for a particular biological activity (e.g., binding affinity).

[0458] To improve antibody affinity, modifications (e.g., substitutions) may be made in HVRs (e.g., CDRs). Such modifications may be made within HVR "hot spots," i.e., residues encoded by codons that undergo frequent mutation during the somatic maturation process (see, e.g., Chowdhury, Methods Mol. Biol. 207:179-196, 2008), and / or residues that contact the antigen, and the resulting variants VH or VL are tested for binding affinity. Affinity maturation by construction and reselection from secondary libraries is described, for example, by Hoogenboom et al. in Methods in Molecular Biology 178:1-37 (O'Brien et al. ed., Human Press, Totowa, NJ, 2001). In some embodiments of affinity maturation, diversity is introduced into the variable genes selected for maturation by any of a variety of methods (e.g., error-prone PCR, chain shuffling, or oligonucleotide-directed mutagenesis). A secondary library is then generated. This library is then screened to identify antibody variants with the desired affinity. Another method for introducing diversity involves an HVR-directed approach, in which several HVR residues (e.g., 4-6 residues at a time) are randomized. HVR residues involved in antigen binding can be specifically identified, for example, using alanine scanning mutagenesis or modeling. In particular, HVR-H3 and HVR-L3 are often targeted.

[0459] In certain embodiments, substitutions, insertions, or deletions may be made within one or more HVRs (e.g., CDRs) so long as such modifications do not substantially reduce the ability of the antibody to bind to antigen. For example, conservative modifications (e.g., conservative substitutions provided herein) that do not substantially reduce binding affinity can be made within HVRs. Such modifications may, for example, be outside of antigen-contacting residues within the HVRs. In certain embodiments of the variant VH and VL sequences provided above, each HVR is unaltered or contains only one, two, or three amino acid substitutions.

[0460] A useful method for identifying antibody residues or regions that can be targeted for mutagenesis is called "alanine scanning mutagenesis," as described in Cunningham et al., Science 244:1081-1085, 1989. In this method, a residue or group of target residues (e.g., charged residues, e.g., Arg, Asp, His, Lys, and Glu) is identified and replaced with neutral or negatively charged amino acids (e.g., Ala or polyalanine) to determine whether antibody-antigen interactions are affected. Further substitutions can be introduced at amino acid positions that demonstrate functional sensitivity to the initial substitution. Alternatively or additionally, a crystal structure of the antigen-antibody complex can be used to identify antibody-antigen contact points. Such contact and neighboring residues can be targeted or excluded as candidates for substitution. Variants can be screened to determine whether they contain desired properties.

[0461] Amino acid sequence insertions include amino- and / or carboxyl-terminal fusions ranging in length from one residue to polypeptides containing 100 or more residues, as well as intrasequence insertions of single or multiple amino acid residues. An example of a terminal insertion is an antibody with an N-terminal methionyl residue. Other insertional variants of antibody molecules include the fusion to the N- or C-terminus of the antibody to an enzyme (e.g., for ADEPT) or a polypeptide which increases the serum half-life of the antibody.

[0462] b) Glycosylation variants In certain embodiments, the antibodies provided herein are modified to increase or decrease the extent to which the antibody is glycosylated. Addition or deletion of glycosylation sites to an antibody can be conveniently accomplished by altering the amino acid sequence such that one or more glycosylation sites are created or removed.

[0463] If the antibody contains an Fc region, the carbohydrate attached thereto can be modified. Natural antibodies produced by mammalian cells typically contain branched, biantennary oligosaccharides that are commonly attached to Asn297 in the CH2 domain of the Fc region via an N-linkage. See, e.g., Wright et al., TIBTECH 15:26-32, 1997. The oligosaccharides can include various carbohydrates, such as mannose, N-acetylglucosamine (GlcNAc), galactose, and sialic acid, as well as fucose attached to the GlcNAc in the "stem" of the biantennary oligosaccharide structure. In some embodiments, modifications of the oligosaccharides in the antibodies disclosed herein can be made to generate antibody variants with specific improved properties.

[0464] In one embodiment, antibody variants are provided that have carbohydrate structures lacking fucose attached (directly or indirectly) to the Fc region. For example, the amount of fucose in such antibodies can be 1% to 80%, 1% to 65%, 5% to 65%, or 20% to 40%. The amount of fucose is determined by calculating the average amount of fucose in the glycan at Asn297 compared to the sum of all glycan structures (e.g., complex, hybrid, and high-mannose structures) attached to Asn297, as measured by MALDI-TOF mass spectrometry, e.g., as described in WO 2008 / 077546. Asn297 refers to an asparagine residue located at approximately position 297 (EU numbering of Fc region residues) within the Fc region; however, Asn297 may also be located approximately ±3 amino acids upstream or downstream of position 297, i.e., between positions 294 and 300, due to minor sequence variations in antibodies. Such fucosylated variants may have improved ADCC function. See, e.g., U.S. Patent Application Publication Nos. 2003 / 0157108 and 2004 / 0093621. Examples of publications related to "defucosylated" or "fucose-deficient" antibody variants include U.S. Patent Application Publication Nos. 2003 / 0157108; WO 2000 / 61739; WO 2001 / 29246; U.S. Patent Application Publication Nos. 2003 / 0115614; 2002 / 0164328; 2004 / 0093621; 0132140; 2004 / 0110704; 2004 / 0110282; 2004 / 0109865; WO 2003 / 085119; 2003 / 084570; 2005 / 035586; 2005 / 035778; 2005 / 053742; 2002 / 031140; Okazaki et al. J. Mol. Biol. 336:1239-1249 (2004); Yamane-Ohnuki et al. Biotech. Bioeng. 87:614. 2004 (2004).Examples of cell lines capable of producing defucosylated antibodies include Lec13 CHO cells, which are deficient in protein fucosylation (Ripka et al. Arch. Biochem. Biophys. 249:533-545, 1986; U.S. Patent Application Publication No. 2003 / 0157108; and WO 2004 / 056312(A1) (especially Example 11)), and knockout cell lines such as CHO cells knocked out of the α-1,6-fucosyltransferase gene FUT8 (see, e.g., Yamane-Ohnuki et al. Biotech. Bioeng. 87:614, 2004; Kanda et al. Biotechnol. Bioeng. 94(4):680-688, 2006; and WO 2003 / 085107).

[0465] Additionally, antibody variants are provided that have biantennary oligosaccharides, for example, biantennary oligosaccharides attached to the Fc region of the antibody, bisected by GlcNAc. Such antibody variants may have reduced fucosylation and / or improved ADCC function. Examples of such antibody variants are described, for example, in WO 2003 / 011878; U.S. Pat. No. 6,602,684; and U.S. Patent Application Publication No. 2005 / 0123546. Antibody variants with at least one galactose residue in the oligosaccharide attached to the Fc region are also provided. Such antibody variants may have improved CDC function. Examples of such antibody variants are described, for example, in WO 1997 / 30087; WO 1998 / 58964; and WO 1999 / 22764.

[0466] c) Fc region variants In certain embodiments, one or more amino acid modifications can be introduced into the Fc region of an antibody provided herein, thereby generating an Fc region variant. The Fc region variant can comprise a human Fc region sequence (e.g., a human IgG1, IgG2, IgG3, or IgG4 Fc region) containing an amino acid modification (e.g., substitution) at one or more amino acid positions.

[0467] In certain embodiments, the present invention contemplates antibody variants that possess some, but not all, effector functions, making them desirable candidates for uses in which in vivo antibody half-life is important but certain effector functions (such as complement and ADCC) are unnecessary or deleterious. In vitro and / or in vivo cytotoxicity assays may be performed to confirm reduced / lack of CDC and / or ADCC activity. For example, Fc receptor (FcR) binding assays can be performed to confirm that the antibody lacks FcγR binding (and thus likely lacks ADCC activity) but retains FcRn binding ability. NK cells, the primary cells for mediating ADCC, express Fc(RIII) only, whereas monocytes express Fc(RI, Fc(RII, and Fc(RIII). FcR expression on hematopoietic cells is summarized in Table 3 on page 464 of Ravetch et al. Annu. Rev. Immunol. 9:457-492, 1991. Non-limiting examples of in vitro assays to assess ADCC activity of a molecule of interest include those described in U.S. Pat. No. 5,500,362 (see, e.g., Hellstrom et al. Proc. Natl. Acad. Sci. USA 83:7059-7063, 1986 and Hellstrom et al. Proc. Natl. Acad. Sci. USA 82:1499-1502, 1985); U.S. Pat. No. 5,821,337 (Bruggemann et al. al. J. Exp. Med. 166:1351-1361, 1987). Alternatively, non-radioactive assay methods may be used (e.g., ACTI for flow cytometry). TMNon-radioactive cytotoxicity assays (see CellTechnology, Inc. Mountain View, CA; and CYTOTOX 96® Non-radioactive Cytotoxicity Assay (Promega, Madison, WI)) are also useful. Useful effector cells for such assays include peripheral blood mononuclear cells (PBMCs) and natural killer (NK) cells. Alternatively, or additionally, ADCC activity of the molecule of interest can be assessed in an in vivo animal model such as that disclosed in Clynes et al. Proc. Natl. Acad. Sci. USA 95:652-656, 1998. C1q binding assays may also be performed to confirm that the antibody is unable to bind C1q and lacks CDC activity. See, e.g., C1q and C3c binding ELISAs in WO 2006 / 029879 and WO 2005 / 100402. To assess complement activation, a CDC assay can be performed (see, e.g., Gazzano-Santoro et al. J. Immunol. Methods 202:163, 1996; Cragg et al. Blood 101:1045-1052, 2003; and Cragg et al. Blood 103:2738-2743, 2004). Determination of FcRn binding and in vivo clearance / half-life can also be performed using methods known in the art (see, e.g., Petkova et al. Intl. Immunol. 18(12):1759-1769, 2006).

[0468] Antibodies with reduced effector function include those containing one or more substitutions at residues 238, 265, 269, 270, 297, 327, and 329 in the Fc region (U.S. Patent No. 6,737,056). Such Fc variants include Fc variants with substitutions at two or more of amino acid positions 265, 269, 270, 297, and 327, including the so-called "DANA" Fc variant in which residues 265 and 297 are substituted with alanine (U.S. Patent No. 7,332,581).

[0469] Certain antibody variants have been described with improved or diminished binding to FcRs (see, e.g., U.S. Pat. No. 6,737,056; WO 2004 / 056312; and Shields et al. J. Biol. Chem. 9(2):6591-6604, 2001).

[0470] In a specific embodiment, the antibody variant comprises an Fc region with one or more amino acid substitutions that improve ADCC, for example substitutions at positions 298, 333 and / or 334 of the Fc region (EU numbering of residues).

[0471] In some embodiments, modifications are made in the Fc region that result in altered (i.e., either improved or decreased) C1q binding and / or complement dependent cytotoxicity (CDC), e.g., as described in U.S. Pat. No. 6,194,551, WO 99 / 51642, and Idusogie et al. J. Immunol. 164:4178-4184, 2000.

[0472] Antibodies with increased half-lives and improved binding to the neonatal Fc receptor (FcRn), which is involved in the transfer of maternal IgG to the fetus (Guyer et al. J. Immunol. 117:587, 1976 and Kim et al. J. Immunol. 24:249, 1994), are described in U.S. Patent Application Publication No. 2005 / 0014934. These antibodies comprise an Fc region with one or more substitutions therein that improve binding of the Fc region to FcRn. Such Fc variants include variants having substitutions at one or more of the following Fc region residues: 238, 256, 265, 272, 286, 303, 305, 307, 311, 312, 317, 340, 356, 360, 362, 376, 378, 380, 382, ​​413, 424, or 434, e.g., a substitution at Fc region residue 434 (U.S. Patent No. 7,371,826).

[0473] For other examples of Fc region variants, see also Duncan et al. Nature 322:738-40, 1988; U.S. Patent No. 5,648,260, U.S. Patent No. 5,624,821, and WO 94 / 29351.

[0474] d) Cysteine ​​Engineered Antibody Variants In certain embodiments, it may be desirable to generate cysteine ​​engineered antibodies, e.g., "thioMAbs," in which one or more residues of an antibody are substituted with cysteine ​​residues. In certain embodiments, the substituted residues occur at accessible sites of the antibody. By replacing these residues with cysteine, reactive thiol groups are placed at accessible sites of the antibody, which can be used to conjugate the antibody to other moieties, such as drug moieties or linker-drug moieties, to generate immunoconjugates, as further described herein. In certain embodiments, any one or more of the following residues can be substituted with cysteine: V205 (Kabat numbering) of the light chain, A118 (EU numbering) of the heavy chain, and S400 (EU numbering) of the heavy chain Fc region. Cysteine ​​engineered antibodies can be generated, for example, as described in U.S. Pat. No. 7,521,541.

[0475] e) Antibody derivative In certain embodiments, the antibodies provided herein may be further modified to contain additional nonproteinaceous moieties known in the art and readily available. Moieties suitable for derivatization of antibodies include, but are not limited to, water-soluble polymers. Non-limiting examples of water-soluble polymers include, but are not limited to, polyethylene glycol (PEG), ethylene glycol / propylene glycol copolymers, carboxymethylcellulose, dextran, polyvinyl alcohol, polyvinylpyrrolidone, poly-1,3-dioxolane, poly-1,3,6-trioxane, ethylene / maleic anhydride copolymers, polyamino acids (either homopolymers or random copolymers), and dextran or poly(n-vinylpyrrolidone), polyethylene glycol, polypropylene glycol homopolymer, polypropylene oxide / ethylene oxide copolymer, polyoxyethylated polyols (e.g., glycerol), polyvinyl alcohol, and mixtures thereof. Polyethylene glycol propionaldehyde may be advantageous during manufacturing due to its stability in water. The polymer may be of any molecular weight and may be branched or unbranched. The number of polymers attached to the antibody can vary, and when multiple polymers are attached, they can be the same or different molecules. Generally, the number and / or type of polymers used for derivatization can be determined based on considerations such as, but not limited to, the particular property or function of the antibody to be improved and whether the antibody derivative will be used therapeutically under defined conditions.

[0476] In another embodiment, a conjugate of an antibody and a non-protein moiety is provided that can be selectively heated by exposure to radiation. In one embodiment, the non-protein moiety is a carbon nanotube (Kam et al. Proc. Natl. Acad. Sci. USA 102:11600-11605, 2005). The radiation can be of any wavelength, including, but not limited to, wavelengths that heat the non-protein moiety to a temperature that is not harmful to normal cells but that kills cells proximal to the antibody-non-protein moiety.

[0477] B. Recombinant Methods and Compositions Antibodies may be produced using recombinant methods and compositions, for example, as described in U.S. Patent No. 4,816,567. In one embodiment, an isolated nucleic acid encoding an anti-IL-33 antibody described herein is provided. Such a nucleic acid may encode an amino acid sequence comprising the VL of the antibody and / or an amino acid sequence comprising the VH of the antibody (e.g., the light chain and / or heavy chain of the antibody). In a further embodiment, one or more vectors (e.g., expression vectors) comprising such nucleic acids are provided. In a further embodiment, a host cell comprising such nucleic acids is provided. In one such embodiment, the host cell comprises (e.g., is transformed with) (1) a vector comprising a nucleic acid encoding an amino acid sequence comprising the VL and an amino acid sequence comprising the VH of the antibody, or (2) a first vector comprising a nucleic acid encoding an amino acid sequence comprising the VL of the antibody and a second vector comprising a nucleic acid encoding an amino acid sequence comprising the VH of the antibody. In one embodiment, the host cell is a eukaryotic cell, such as a Chinese hamster ovary (CHO) cell, a 293 cell, or a lymphoid cell (e.g., a Y0, NS0, or Sp20 cell). In one embodiment, a method of making an anti-IL-33 antibody is provided, wherein the method comprises culturing a host cell comprising nucleic acid encoding the antibody under conditions suitable for expression of the antibody, as described above, and optionally recovering the antibody from the host cell (or host cell culture medium).

[0478] For recombinant production of an anti-IL-33 antibody, nucleic acid encoding the antibody is isolated, e.g., as described above, and inserted into one or more vectors for further cloning and / or expression in a host cell. Such nucleic acid can be readily isolated and sequenced using conventional procedures (e.g., by using oligonucleotide probes capable of specifically binding to genes encoding the antibody heavy and light chains).

[0479] Suitable host cells for cloning or expressing antibody-encoding vectors include prokaryotic or eukaryotic cells as described herein. For example, antibodies may be produced in bacteria, particularly if glycosylation and effector functions are not required. For expression of antibody fragments and polypeptides in bacteria, see, e.g., U.S. Patent Nos. 5,648,237, 5,789,199, and 5,840,523. (See also Charlton, Methods in Molecular Biology, Vol. 248 (BKC Lo, ed., Humana Press, Totowa, NJ, 2003), pp. 245-254, which describes the expression of antibody fragments in E. coli.) After expression, the antibody can be isolated from the bacterial cell paste in a soluble fraction and further purified.

[0480] In addition to prokaryotes, eukaryotic organisms such as filamentous fungi and yeast are suitable cloning or expression hosts for antibody-encoding vectors, including bacterial and yeast strains that have been "humanized" in their glycosylation pathways to produce antibodies with partially or fully human glycosylation patterns. See Gerngross Nat. Biotech. 22:1409-1414, 2004 and Li et al. Nat. Biotech. 24:210-215, 2006.

[0481] Suitable host cells for expressing glycosylated antibodies are also derived from multicellular organisms (invertebrates and vertebrates). Examples of invertebrate cells include plant cells and insect cells. Numerous baculovirus strains have been identified that can be used with insect cells, particularly for transfection of Spodoptera frugiperda cells.

[0482] Plant cell cultures can also be utilized as hosts. See, e.g., U.S. Patent Nos. 5,959,177, 6,040,498, 6,420,548, 7,125,978, and 6,417,429 (PLANTIBODIES FOR PRODUCING ANTIBODIES IN TRANSGENIC PLANTS). TM (which describes the technique).

[0483] Vertebrate cells may also be used as hosts, for example, mammalian cell lines adapted to grow in suspension may be useful. Other examples of useful mammalian host cell lines include the SV40 (COS-7) transformed monkey kidney CV1 line; human embryonic kidney lines (e.g., 293 or 293 cells described in Graham et al., J. Gen Virol. 36:59, 1977); baby hamster kidney cells (BHK); mouse Sertoli cells (e.g., TM4 cells described in Mather, Biol. Reprod. 23:243-251, 1980); monkey kidney cells (CV1); African green monkey kidney cells (VERO-76); human cervical carcinoma cells (HELA); canine kidney cells (MDCK); buffalo rat liver cells (BRL3A); human lung cells (W138); human hepatocytes (Hep G2); mouse mammary tumor (MMT060562); TRI cells, e.g., as described in Mather et al., Annals NY Acad. Sci. 383:44-68, 1982; MRC5 cells; and FS4 cells. Other useful mammalian host cell lines include DHFR - and myeloma cell lines such as Y0, NS0, and Sp2 / 0. For a review of specific mammalian host cell lines suitable for antibody production, see, e.g., Yazaki et al., Methods in Molecular Biology, Vol. 248 (BKC Lo, ed., Humana Press, Totowa, NJ), pp. 255-268, 2003.

[0484] C. Assay The anti-IL-33 antibodies provided herein may be identified, screened, or characterized for their physical / chemical properties and / or biological activities by various assays known in the art.

[0485] 1: Binding assays and other assays In one embodiment, the anti-IL-33 antibodies disclosed herein are tested for their antigen binding activity by known methods, such as, for example, ELISA, Western blot, etc.

[0486] In another aspect, a competition assay can be used to identify antibodies that compete with the anti-IL-33 antibodies disclosed herein for binding to IL-33. In certain embodiments, such competing antibodies bind to the same epitope (e.g., a linear or conformational epitope) bound by the anti-IL-33 antibodies disclosed herein. Detailed exemplary methods for mapping antibody-binding epitopes are provided in Morris, "Epitope Mapping Protocols," in Methods in Molecular Biology Vol. 66 (Humana Press, Totowa, NJ), 1996.

[0487] In an exemplary competitive assay, immobilized IL-33 is incubated in a solution containing a first labeled antibody that binds to IL-33 and a second unlabeled antibody being tested for its ability to compete with the first antibody for binding to IL-33. The second antibody may be present in hybridoma supernatant. As a control, immobilized IL-33 is incubated in a solution containing the first labeled antibody but not the second unlabeled antibody. After incubation under conditions that allow binding of the first antibody to IL-33, excess unbound antibody is removed and the amount of label bound to the immobilized IL-33 is measured. If the amount of label bound to the immobilized IL-33 is substantially reduced in the test sample compared to the control sample, this indicates that the second antibody competes with the first antibody for binding to IL-33. See Harlow et al., Antibodies: A Laboratory Manual Ch. 14 (Cold Spring Harbor Laboratory, Cold Spring Harbor, NY), 1988.

[0488] 2: Activity assay In one aspect, assays are provided for identifying anti-IL-33 antibodies having biological activity. Biological activity can include, for example, binding to IL-33 (e.g., IL-33 in the bloodstream) or peptide fragments thereof, either in vivo, in vitro, or ex vivo. In other embodiments, biological activity can include blocking or neutralizing IL-33 or preventing IL-33 from binding to a ligand, e.g., a receptor (e.g., IL-33 receptor ST2 and / or IL-1RAcP). In some embodiments, biological activity can include binding to site 1 on IL-33 and blocking binding to IL-33 receptors (i.e., ST2 and / or IL-1RAcP). Antibodies with such biological activity in vivo and / or in vitro are also provided. In certain embodiments, the antibodies disclosed herein are tested for such biological activity. In some embodiments, the anti-IL-33 antibodies disclosed herein are tested for inhibition in a cell-based IL-33 blocking assay. In some embodiments, the anti-IL-33 antibodies disclosed herein are capable of binding to IL-33 in cell-based blocking assays (e.g., the IL-33 HEK-BLUE antibody described herein). TM In some embodiments, the antibodies disclosed herein are tested for inhibition of IL-33-induced reporter activity in a primary cell-based assay (see, e.g., Examples 3 and 6). In some embodiments, the antibodies disclosed herein are tested for inhibition of IL-33 activity in primary cells, such as in a primary NK cell assay (see, e.g., Example 8, section C of WO 2016 / 077381) or a primary basophil assay (see, e.g., Example 8, section D of WO 2016 / 077381). In some embodiments, the antibodies disclosed herein are tested for inhibition of IL-33 binding to the IL-33 receptor in a competitive binding ELISA (see, e.g., Example 8, section F of WO 2016 / 077381).

[0489] D. Immunoconjugates The present invention also provides immunoconjugates comprising an anti-IL-33 antibody provided herein conjugated to one or more cytotoxic agents, such as a chemotherapeutic agent or drug, a growth inhibitory agent, a toxin (e.g., a protein toxin, an enzymatically active toxin of bacterial, fungal, plant, or animal origin, or fragments thereof), or a radioactive isotope.

[0490] In one embodiment, the immunoconjugate comprises an antibody or a compound selected from the group consisting of maytansinoids (see U.S. Pat. Nos. 5,208,020, 5,416,064, and EP 0425235); auristatins, such as the monomethyl auristatin drug moieties DE and DF (MMAE and MMAF) (see U.S. Pat. Nos. 5,635,483, 5,780,588, and 7,498,298); dolastatins; calicheamicin or a derivative thereof (see U.S. Pat. Nos. 5,712,374, 5,714,586, 5,739,116, 5,767,285, 5,770,701, 5,770,710, 5,773,001, and 5,877,296; Hinman et al. al., Cancer Res. 53:3336-3342 (1993); and Cancer Res. 58:2925-2928 (1998)); anthracyclines such as daunomycin or doxorubicin (Kratz et al., Current Med. Chem. 13:477-523, 2006; Jeffrey et al., Bioorganic & Med. Chem. Letters 16:358-362 (2006); Torgov et al., Bioconj. Chem. 16:717-721, 2005; Nagy et al., Proc. Natl. Acad. Sci. USA 97:829-834, 2000; Dubowchik et al., Bioorg. & Med. Chem. Letters 12:1529-1532, 2002; King et al., J. Med. Chem. 45:4336-4343, 2002; and U.S. Patent No. 6,630,579); methotrexate; vindesine; taxanes such as docetaxel, paclitaxel, larotaxel, tesetaxel, and ortataxel; trichothecenes; and antibody-drug conjugates (ADCs) conjugated to one or more agents, including, but not limited to, CC1065.

[0491] In another embodiment, the immunoconjugate comprises an antibody described herein conjugated to an enzymatically active toxin or fragment thereof, including, but not limited to, diphtheria A chain, a nonbinding active fragment of diphtheria toxin, exotoxin A chain (from Pseudomonas aeruginosa), ricin A chain, abrin A chain, modeccin A chain, alpha-sarcin, Aleurites fordii protein, dianthin protein, Phytolacca americana proteins (PAPI, PAPII, and PAP-S), Momordica charantia inhibitor, curcin, crotin, Sapaonaria officinalis inhibitor, gelonin, mitogenin, restrictocin, phenomycin, enomycin, and a trichothecene.

[0492] In another embodiment, the immunoconjugate comprises an antibody described herein conjugated to a radioactive atom to form a radioconjugate. A variety of radioisotopes are available for the production of radioconjugates. Examples include At 211 , I 131 , I 125 , Y 90 ,Re 186 ,Re 188 , Sm 153 , Bi 212 , P 32 , Pb 212 When radioactive conjugates are used for detection, they include radioactive atoms for scintigraphic studies, such as technetium-99m (tc99m) or I 123 , or nuclear magnetic resonance (NMR) imaging (also known as magnetic resonance imaging, mri) spin labels, such as, again, iodine-123, iodine-131, indium-111, fluorine-19, carbon-13, nitrogen-15, oxygen-17, gadolinium, manganese, or iron.

[0493] Conjugates of antibodies and cytotoxic agents can be made using a variety of bifunctional protein coupling agents, such as N-succinimidyl-3-(2-pyridyldithio)propionate (SPDP), succinimidyl-4-(N-maleimidomethyl)cyclohexane-1-carboxylate (SMCC), iminothiolane (IT), bifunctional derivatives of imidoesters (e.g., dimethyl adipimidate HCl), active esters (e.g., disuccinimidyl suberate), aldehydes (e.g., glutaraldehyde), bisazide compounds (e.g., bis(p-azidobenzoyl)hexanediamine), bis-diazonium derivatives (e.g., bis-(p-diazoniumbenzoyl)-ethylenediamine), diisocyanates (e.g., toluene 2,6-diisocyanate), and diactive fluorine compounds (e.g., 1,5-difluoro-2,4-dinitrobenzene). For example, ricin immunotoxins can be prepared as described in Vitetta et al. Science 238:1098, 1987. Carbon-14-labeled 1-isothiocyanatobenzyl-3-methyldiethylenetriaminepentaacetic acid (MX-DTPA) is an exemplary chelating agent for conjugating radionucleotides to antibodies. See International Publication No. WO 94 / 11026. The linker may also be a "cleavable linker" that facilitates the release of the cytotoxic drug within the cell. For example, an acid-labile linker, peptidase-sensitive linker, photolabile linker, dimethyl linker, or disulfide-containing linker (see, e.g., Chari et al. Cancer Res. 52:127-131, 1992; U.S. Patent No. 5,208,020) can be used.

[0494] The immunoconjugates or ADCs herein expressly contemplate, but are not limited to, such conjugates prepared with crosslinker reagents including, but not limited to, BMPS, EMCS, GMBS, HBVS, LC-SMCC, MBS, MPBH, SBAP, SIA, SIAB, SMCC, SMPB, SMPH, sulfo-EMCS, sulfo-GMBS, sulfo-KMUS, sulfo-MBS, sulfo-SIAB, sulfo-SMCC, and sulfo-SMPB, and SVSB (succinimidyl-(4-vinylsulfone)benzoate), which are commercially available (e.g., from Pierce Biotechnology, Inc., Rockford, IL, USA).

[0495] E. Methods and Compositions for Diagnostics and Detection In certain embodiments, any of the anti-IL-33 antibodies provided herein is useful for detecting the presence of IL-33 in a biological sample. As used herein, the term "detection" encompasses quantitative or qualitative detection. In certain embodiments, the biological sample comprises cells or tissues, such as smooth muscle cells, epithelial cells, endothelial cells, blood, blood cells (e.g., macrophages, innate type II (ILC2) cells, mast cells, basophils, eosinophils, and dendritic cells), central nervous system cells (e.g., glial cells), or ocular cells (e.g., retinal cells (e.g., Müller cells or retinal pigment epithelial (RPE) cells) and ocular vascular endothelial cells).

[0496] In one embodiment, an anti-IL-33 antibody is provided for use in a method of diagnosis or detection. In a further aspect, a method of detecting the presence of IL-33 in a biological sample is provided. In certain embodiments, the method comprises contacting a biological sample with an anti-IL-33 antibody described herein under conditions that allow binding of the anti-IL-33 antibody to IL-33, and detecting whether a complex is formed between the anti-IL-33 antibody and IL-33. Such a method may be an in vitro method or an in vivo method. In one embodiment, for example, when IL-33 is a biomarker for patient selection, the anti-IL-33 antibody is used to select subjects eligible for treatment with the anti-IL-33 antibody.

[0497] Exemplary disorders that can be diagnosed using the antibodies disclosed herein include, for example, ocular disorders (e.g., age-related macular degeneration (AMD) or ocular retinopathy), inflammatory conditions (e.g., asthma, sepsis, septic shock, atopic dermatitis, allergic rhinitis, rheumatoid arthritis, and chronic obstructive pulmonary disease (COPD)), immune disorders (e.g., asthma, rheumatoid arthritis, allergies, atopic allergies, anaphylaxis, anaphylactic shock, allergic rhinitis, psoriasis, inflammatory bowel disease ( IBD), Crohn's disease, diabetes, and liver disease), fibrotic disorders (e.g., pulmonary fibrosis (e.g., idiopathic pulmonary fibrosis)), eosinophilic disorders (e.g., eosinophil-associated gastrointestinal disorders (EGIDs) including eosinophilic esophagitis), infections (e.g., helminth infections, protozoan infections, and viral infections), pain (e.g., inflammatory pain), central nervous system disorders (e.g., Alzheimer's disease), and solid tumors (e.g., tumors of the breast, colon, prostate, lung, kidney, liver, pancreas, stomach, intestine, brain, bone, and skin). In some cases, ocular disorders that may be diagnosed using the antibodies disclosed herein include AMD (e.g., wet AMD, dry AMD, intermediate AMD, advanced AMD, and geographic atrophy (GA)), retinopathies (e.g., diabetic retinopathy (DR), retinopathy of prematurity (ROP), and high-altitude DR), polypoidal choroidal vasculopathy (PCV), diabetic macular edema, dry eye disease, Behcet's disease, retinal detachment, glaucoma, uveitis (e.g., infectious and non-infectious uveitis), retinitis pigmentosa, Leber's congenital amaurosis, Stargardt's disease, traumatic eye injury, and conjunctivitis (e.g., infectious conjunctivitis, non-infectious conjunctivitis, and allergic conjunctivitis).

[0498] In some cases, the eye disorder includes AMD (including wet AMD, dry AMD, and GA), retinopathy (e.g., DR and ROP), PCV, diabetic macular edema, dry eye disease, Behcet's disease, allergic conjunctivitis, and retinal detachment.

[0499] In other instances, the eye disorder includes intermediate AMD, advanced AMD, glaucoma, uveitis (e.g., infectious and non-infectious uveitis), retinitis pigmentosa, Leber's congenital amaurosis, Stargardt's disease, high altitude diabetic retinopathy, traumatic eye injury, and conjunctivitis (e.g., infectious and non-infectious conjunctivitis).

[0500] In certain embodiments, labeled anti-IL-33 antibodies are provided. Labels include, but are not limited to, labels or moieties that are directly detected (e.g., fluorescent labels, chromogenic labels, electron-dense labels, chemiluminescent labels, radioactive labels, etc.) and moieties that are indirectly detected via enzymatic reactions or molecular interactions (e.g., enzymes or ligands, etc.). Exemplary labels include radioisotopes, 32 P, 14 C. 125 I, 3 H, and 131 These include, but are not limited to, I, rare earth chelates or fluorophores such as fluorescein and its derivatives, rhodamine and its derivatives, dansyl, umbelliferone, luciferases such as firefly luciferase and bacterial luciferase (U.S. Pat. No. 4,737,456), luciferin, 2,3-dihydrophthalazinediones, horseradish peroxidase (HRP), alkaline phosphatase, β-galactosidase, glucoamylase, lysozyme, sugar oxidases such as glucose oxidase, galactose oxidase, and glucose-6-phosphate dehydrogenase, heterocyclic oxidases such as uricase and xanthine oxidase conjugated to enzymes that utilize hydrogen peroxide to oxidize dye precursors such as HRP, lactoperoxidase, or microperoxidase, biotin / avidin, spin labels, bacteriophage labels, stable free radicals, and the like.

[0501] F. Pharmaceutical Formulations Pharmaceutical formulations of the anti-IL-33 antibodies disclosed herein are prepared in the form of a lyophilized formulation or aqueous solution by mixing the antibody having the desired degree of purity with one or more optional pharmaceutically acceptable carriers (see, for example, Remington's Pharmaceutical Sciences 16th edition, Osol, A. Ed., 1980). Pharmaceutically acceptable carriers are generally non-toxic to recipients at the dosages and concentrations used, and may include buffers such as phosphate, citrate, and other organic acids; antioxidants including ascorbic acid and methionine; preservatives (such as octadecyldimethylbenzylammonium chloride; hexamethonium chloride; benzalkonium chloride; benzethonium chloride; phenol, butyl, or benzyl alcohol; alkylparabens such as methyl or propylparaben; catechol; resorcinol; cyclohexanol; 3-pentanol; and m-cresol); low-molecular-weight (less than about 10 residues) polypeptides; serum Examples of suitable pharmaceutically acceptable carriers include, but are not limited to, proteins such as albumin, gelatin, or immunoglobulins; hydrophilic polymers such as polyvinylpyrrolidone; amino acids such as glycine, glutamine, asparagine, histidine, arginine, or lysine; monosaccharides, disaccharides, and other carbohydrates including glucose, mannose, or dextrin; chelating agents such as EDTA; sugars such as sucrose, mannitol, trehalose, or sorbitol; salt-forming counterions such as sodium; metal complexes (e.g., Zn-protein complexes); and / or non-ionic surfactants such as polyethylene glycol (PEG). Exemplary pharmaceutically acceptable carriers herein further include intercalating drug dispersants, such as soluble neutral active hyaluronidase glycoproteins (sHASEGPs), e.g., human soluble PH-20 hyaluronidase glycoproteins, such as rHuPH20 (HYLENEX®, Baxter International, Inc.). Some exemplary sHASEGPs, including rHuPH20, and methods of use are described in U.S. Patent Application Publication Nos. 2005 / 0260186 and 2006 / 0104968.In one embodiment, the sHASEGP is combined with one or more additional glycosaminoglycanases, such as chondroitinases.

[0502] Exemplary lyophilized antibody formulations are described in U.S. Patent No. 6,267,958. Aqueous antibody formulations include those described in U.S. Patent No. 6,171,586 and WO 2006 / 044908, the latter formulation comprising a histidine acetate buffer.

[0503] The formulations herein may also contain two or more active ingredients as needed for the particular indication being treated, preferably those with complementary activities that do not adversely affect each other. For example, it may be desirable to further provide an ST2 binding antagonist, a complement pathway inhibitor (e.g., a factor D binding antagonist), an HtrA1 binding antagonist, a VEGF antagonist, a tryptase-beta binding antagonist, a chemoattractant receptor-like molecule expressed on Th2 cells (CRTH2) binding antagonist, an interleukin-13 (IL-13) binding antagonist, an interleukin-17 (IL-17) binding antagonist, a JAK1 antagonist, and / or an interleukin-5 (IL-5) binding antagonist. In some cases, the complement pathway inhibitor is a factor D binding antagonist. In some cases, the Factor D binding antagonist is an anti-Factor D antibody or an antigen-binding fragment thereof, e.g., as described in Section G, "Therapeutic Methods and Compositions," below. In some cases, the HtrA1 binding antagonist is an anti-HtrA1 antibody or an antigen-binding fragment thereof, e.g., as described in Section G, "Therapeutic Methods and Compositions," below. In some cases, the anti-HtrA1 antibody fragment is a Fab, Fab'-SH, Fv, scFv, or (Fab')2 fragment. In some cases, the Factor D antibody fragment is a Fab, Fab'-SH, Fv, scFv, or (Fab')2 fragment. In some cases, the VEGF antagonist is an anti-VEGF antibody or an antigen-binding fragment thereof, e.g., as described in Section G, "Therapeutic Methods and Compositions," below. In some cases, the anti-VEGF antibody fragment is a Fab, Fab'-SH, Fv, scFv, or (Fab')2 fragment. In some cases, the VEGF antagonist is an anti-VEGF receptor antibody or an antigen-binding fragment thereof. In some cases, the anti-VEGF receptor antibody fragment is a Fab, Fab'-SH, Fv, scFv, or (Fab')2 fragment. Such active ingredients are suitably present in combination in amounts effective for the intended purpose.

[0504] The active ingredient may be encapsulated in microcapsules prepared, for example, by coacervation techniques or by interfacial polymerization (e.g., hydroxymethylcellulose or gelatin microcapsules and poly(methyl methacrylate) microcapsules, respectively), colloidal drug delivery systems (e.g., liposomes, albumin microspheres, microemulsions, nanoparticles, and nanocapsules), or macroemulsions. Such techniques are disclosed in Remington's Pharmaceutical Sciences 16th edition, Osol, A. Ed., 1980.

[0505] Sustained-release preparations may be prepared. Suitable examples of sustained-release preparations include semipermeable matrices of solid hydrophobic polymers containing the antibody, which matrices are in the form of shaped articles, e.g., films, or microcapsules.

[0506] For ocular delivery, the antibodies disclosed herein can be combined with, for example, ophthalmologically acceptable preservatives, cosolvents, surfactants, viscosity enhancers, penetration enhancers, buffers, sodium chloride, and / or water. Preservatives may be included, for example, to inhibit microbial contamination during use. Suitable preservatives include edetate disodium, methylparaben, propylparaben, sorbic acid, phenylethyl alcohol, chlorobutanol, polyquaternium-1, or other agents known in the art. Such preservatives are typically used at levels of 0.001 to 1.0 w / v%. In some cases, the pharmaceutical formulations disclosed herein are preservative-free. In some cases, compositions intended for topical administration to the eye can be prepared as eye drops or eye ointments. In some cases, the total amount of antibody is about 0.001 to 1.0% (w / w) of such a formulation, e.g., about 0.01 to about 1.0% (w / w).

[0507] Formulations to be used for in vivo administration are generally sterile. Sterility may be readily accomplished, for example, by filtration through sterile filtration membranes.

[0508] An anti-IL-33 antibody (eg, any anti-IL-33 antibody disclosed herein) can be formulated in a polymer formulation.

[0509] Any suitable concentration of any antibody disclosed herein can be used in a composition (e.g., a pharmaceutical composition). For example, the concentration of an antibody in a composition disclosed herein can range from about 1 mg / mL to about 400 mg / mL (e.g., about 1 mg / mL to about 400 mg / mL, about 1 mg / mL to about 375 mg / mL, about 1 mg / mL to about 350 mg / mL, about 1 mg / mL to about 325 mg / mL, about 1 mg / mL to about 300 mg / mL, about 1 mg / mL to about 275 mg / mL, about 1 mg / mL to about 250 mg / mL, about 1 mg / mL to about 225 mg / mL, about 1 mg / mL to about 200 mg / mL, about 1 mg / mL to about 175 mg / mL, about 1mg / mL to about 150mg / mL, about 1mg / mL to about 125mg / mL, about 1mg / mL to about 100mg / mL, about 1mg / mL to about 75mg / mL, about 1mg / mL to about 50mg / mL, about 1mg / mL to about 25mg / mL, about 25mg / mL to about 350m g / mL, about 25 mg / mL to about 325 mg / mL, about 25 mg / mL to about 300 mg / mL, about 25 mg / mL to about 275 mg / mL, about 25 mg / mL to about 250 mg / mL, about 25 mg / mL to about 225 mg / mL, about 25 mg / mL to about 200 mg / mL , about 25 mg / mL to about 175 mg / mL, about 25 mg / mL to about 150 mg / mL, about 25 mg / mL to about 125 mg / mL, about 25 mg / mL to about 100 mg / mL, about 25 mg / mL to about 75 mg / mL, about 25 mg / mL to about 50 mg / mL, about 50 mg / mL~about 350mg / mL, about 50mg / mL~about 325mg / mL, about 50mg / mL~about 300mg / mL, about 50mg / mL~about 275mg / mL, about 50mg / mL~about 250mg / mL, about 50mg / mL~about 225mg / mL, about 50mg / mL~ Approximately 200mg / mL, approximately 50mg / mL to approximately 175mg / mL, approximately 50mg / mL to approximately 150mg / mL, approximately 50mg / mL to approximately 125mg / mL, approximately 50mg / mL to approximately 100mg / mL, approximately 50mg / mL to approximately 75mg / mL, approximately 75mg / mL to approximately 350m g / mL, about 75 mg / mL to about 325 mg / mL, about 75 mg / mL to about 300 mg / mL, about 75 mg / mL to about 275 mg / mL, about 75 mg / mL to about 250 mg / mL, about 75 mg / mL to about 225 mg / mL, about 75 mg / mL to about 200 mg / mL,The concentration may be about 75 mg / mL to about 175 mg / mL, about 75 mg / mL to about 150 mg / mL, about 75 mg / mL to about 125 mg / mL, about 75 mg / mL to about 100 mg / mL, about 100 mg / mL to about 350 mg / mL, about 100 mg / mL to about 325 mg / mL, about 100 mg / mL to about 300 mg / mL, about 100 mg / mL to about 275 mg / mL, about 100 mg / mL to about 250 mg / mL, about 100 mg / mL to about 225 mg / mL, about 100 mg / mL to about 200 mg / mL, about 100 mg / mL to about 175 mg / mL, about 100 mg / mL to about 150 mg / mL, about 100 mg / mL to about 125 mg / mL, or about 150 mg / mL to about 175 mg / mL). In some cases, the antibody is at a concentration of about 50 mg / mL to about 300 mg / mL (e.g., about 50 mg / mL, about 60 mg / mL, about 70 mg / mL, about 80 mg / mL, about 90 mg / mL, about 100 mg / mL, about 110 mg / mL, about 120 mg / mL, about 130 mg / mL, about 140 mg / mL, about 150 mg / mL, about 160 mg / mL, about 170 mg / mL, about 180 mg / mL, about 190 mg / mL, about 200 mg / mL, about 210 mg / mL, about 220 mg / mL, about 230 mg / mL, about 240 mg / mL, about 250 mg / mL, about 260 mg / mL, about 270 mg / mL, about 280 mg / mL, about 290 mg / mL, or about 300 mg / mL). In some instances, the antibody has a concentration of about 175 mg / mL to about 225 mg / mL (e.g., about 175 mg / mL, about 176 mg / mL, about 177 mg / mL, about 178 mg / mL, about 179 mg / mL, about 180 mg / mL, about 181 mg / mL, about 182 mg / mL, about 183 mg / mL, about 184 mg / mL, about 185 mg / mL, about 186 mg / mL, about 187 mg / mL, about 188 mg / mL, about 189 mg / mL, about 190 mg / mL, about 200 mg / mL, about 210 mg / mL, about 211 mg / mL, about 212 mg / mL, about 213 mg / mL, about 214 mg / mL, about 215 mg / mL, about 216 mg / mL, about 217 mg / mL, about 218 mg / mL, about 219 mg / mL, about 220 mg / ...

Claims

1. An isolated antibody, or antigen-binding fragment thereof, that specifically binds to IL-33, wherein the antibody has a binding domain comprising a heavy chain variable (VH) domain and a light chain variable (VL) domain, and the antibody has the following six complementarity-determining regions (CDRs): (a) CDR-H1 comprising the amino acid sequence of NYWMT (SEQ ID NO: 1); (b) CDR-H2 comprising the amino acid sequence SITYTGGGTYYPDSVKG (SEQ ID NO: 2); (c) CDR-H3 comprising the amino acid sequence ANYYYNTYGGFPY (SEQ ID NO: 3); (d) CDR-L1 comprising the amino acid sequence of LASEGFSNDL A (SEQ ID NO: 4); (e) CDR-L2 comprising the amino acid sequence of AASRLQD (SEQ ID NO: 5); and (f) CDR-L3 comprising the amino acid sequence of QQGSKYPLT (SEQ ID NO: 6) 1. An antibody, or antigen-binding fragment thereof, comprising a binding domain comprising:

2. An isolated antibody, or antigen-binding fragment thereof, that specifically binds to IL-33, wherein the antibody comprises: (a) a VH domain comprising an amino acid sequence having at least 95% sequence identity to the amino acid sequence of SEQ ID NO: 7; (b) a VL domain comprising an amino acid sequence having at least 95% sequence identity to the amino acid sequence of SEQ ID NO: 8; or (c) a binding domain comprising the VH domain of (a) and the VL domain of (b).

3. The VH domain is (a) EVQLVX １ SGX ２ X ３ X ４ X ５ X ６ PGX ７ SX ８ X ９ X １０ SCX １１ FR-H1 comprising the amino acid sequence of ASGFTFN (SEQ ID NO: 9), １ is E or Q; X ２ is G or A; X ３ is G or E; X ４ is L or V; X ５ is V or K; X ６ is Q or K; X ７ is G, A, or T; X ８ is L or V; X ９ is R or K; X １０ is L or V; X １１ is A, K, or L); (b) WX １ RQAPGX ２ GLEWX ３ X ４ FR-H2 comprising the amino acid sequence of (SEQ ID NO: 10) １ is I or V; X ２ is K or Q; X ３ is V, M, or I; X ４ is A or G); (c) RX １ TX ２ X ３ RDX ４ X ５ X ６ X ７ X ８ X ９ YX １０ X １１ X １２ X １３ SLRX １４ EDTAX １５ FR-H3 comprising the amino acid sequence of YYCTR (SEQ ID NO: 11), １ is F or V; X ２ is I or M; X ３ is S or T; X ４ is D, N, or T; X ５ is A or S; X ６ is K or T; X ７ is S or N; X ８ is S or T; X ９ is L or V; X １０ is L or M; X １１ is Q or E; X １２ is M or L; X １３ is N or S; X １４ is A or S; X １５ is V or T); and (d) FR-H4 containing the amino acid sequence WGQGTLVTVSS (SEQ ID NO: 12) The antibody of claim 1 or 2, comprising:

4. The VH domain is (a) FR-H1 comprising the amino acid sequence of EVQLVESGGGLVQPGGSLRLSCAASGFTFN (SEQ ID NO: 17); (b) FR-H2 comprising the amino acid sequence of WIRQAPGKGLEWVA (SEQ ID NO: 18); (c) FR-H3 comprising the amino acid sequence of RFTISRDDAKSSLYLQMNSLRAEDTAVYYCTR (SEQ ID NO: 19); and (d) FR-H4 containing the amino acid sequence WGQGTLVTVSS (SEQ ID NO: 12) The antibody according to any one of claims 1 to 3, comprising:

5. The antibody of any one of claims 1 to 3, wherein the VH domain comprises the amino acid sequence of SEQ ID NO:

7.

6. The VH domain is (a) FR-H1 comprising the amino acid sequence of EVQLVESGGGLVQPGGSLRLSCAASGFTFN (SEQ ID NO: 17); (b) FR-H2 comprising the amino acid sequence of WVRQAPGKGLEWVA (SEQ ID NO: 39); (c) FR-H3 comprising the amino acid sequence of RFTISRDNAKNSLYLQMNSLRAEDTAVYYCTR (SEQ ID NO: 40); and (d) FR-H4 containing the amino acid sequence WGQGTLVTVSS (SEQ ID NO: 12) The antibody according to any one of claims 1 to 3, comprising:

7. The antibody of any one of claims 1 to 3, wherein the VH domain comprises the amino acid sequence of SEQ ID NO:

41.

8. The VH domain is (a) FR-H1 comprising the amino acid sequence of EVQLVESGGGLVQPGGSLRLSCAASGFTFN (SEQ ID NO: 17); (b) FR-H2 comprising the amino acid sequence of WIRQAPGKGLEWIA (SEQ ID NO: 42); (c) FR-H3 comprising the amino acid sequence of RFTISRDDAKSSLYLQMNSLRAEDTAVYYCTR (SEQ ID NO: 19); and (d) FR-H4 containing the amino acid sequence WGQGTLVTVSS (SEQ ID NO: 12) The antibody according to any one of claims 1 to 3, comprising:

9. The antibody of any one of claims 1 to 3, wherein the VH domain comprises the amino acid sequence of SEQ ID NO:

43.

10. The VH domain is (a) FR-H1 comprising the amino acid sequence of EVQLVESGGGLVQPGGSLRLSCAASGFTFN (SEQ ID NO: 17); (b) FR-H2 comprising the amino acid sequence of WVRQAPGKGLEWVA (SEQ ID NO: 39); (c) FR-H3 comprising the amino acid sequence of RFTISRDDAKSSLYLQMNSLRAEDTAVYYCTR (SEQ ID NO: 19); and (d) FR-H4 containing the amino acid sequence WGQGTLVTVSS (SEQ ID NO: 12) The antibody according to any one of claims 1 to 3, comprising:

11. The antibody of any one of claims 1 to 3, wherein the VH domain comprises the amino acid sequence of SEQ ID NO:

44.

12. The VH domain is (a) FR-H1 comprising the amino acid sequence of EVQLVESGGGLVQPGGSLRLSCAASGFTFN (SEQ ID NO: 17); (b) FR-H2 comprising the amino acid sequence of WVRQAPGKGLEWVA (SEQ ID NO: 39); (c) FR-H3 comprising the amino acid sequence of RFTISRDDAKNSLYLQMNSLRAEDTAVYYCTR (SEQ ID NO: 45); and (d) FR-H4 containing the amino acid sequence WGQGTLVTVSS (SEQ ID NO: 12) The antibody according to any one of claims 1 to 3, comprising:

13. The antibody of any one of claims 1 to 3, wherein the VH domain comprises the amino acid sequence of SEQ ID NO:

46.

14. The VH domain is (a) FR-H1 comprising the amino acid sequence of EVQLVESGGGLVQPGGSLRLSCAASGFTFN (SEQ ID NO: 17); (b) FR-H2 comprising the amino acid sequence of WVRQAPGKGLEWVA (SEQ ID NO: 39); (c) FR-H3 comprising the amino acid sequence of RFTISRDNAKSSLYLQMNSLRAEDTAVYYCTR (SEQ ID NO: 47); and (d) FR-H4 containing the amino acid sequence WGQGTLVTVSS (SEQ ID NO: 12) The antibody according to any one of claims 1 to 3, comprising:

15. The antibody of any one of claims 1 to 3, wherein the VH domain comprises the amino acid sequence of SEQ ID NO:

48.

16. The VH domain is (a) FR-H1 comprising the amino acid sequence of EVQLVESGGGLVQPGGSLRLSCAASGFTFN (SEQ ID NO: 17); (b) FR-H2 comprising the amino acid sequence of WVRQAPGKGLEWIA (SEQ ID NO: 49); (c) FR-H3 comprising the amino acid sequence of RFTISRDDAKSSLYLQMNSLRAEDTAVYYCTR (SEQ ID NO: 19); and (d) FR-H4 containing the amino acid sequence WGQGTLVTVSS (SEQ ID NO: 12) The antibody according to any one of claims 1 to 3, comprising:

17. The antibody of any one of claims 1 to 3, wherein the VH domain comprises the amino acid sequence of SEQ ID NO:

50.

18. The VH domain is (a) FR-H1 comprising the amino acid sequence of EVQLVESGGGLVQPGGSLRLSCAASGFTFN (SEQ ID NO: 17); (b) FR-H2 comprising the amino acid sequence of WVRQAPGKGLEWIA (SEQ ID NO: 49); (c) FR-H3 comprising the amino acid sequence of RFTISRDDSKSTLYLQMNSLRAEDTAVYYCTR (SEQ ID NO: 51); and (d) FR-H4 containing the amino acid sequence WGQGTLVTVSS (SEQ ID NO: 12) The antibody according to any one of claims 1 to 3, comprising:

19. The antibody of any one of claims 1 to 3, wherein the VH domain comprises the amino acid sequence of SEQ ID NO:

52.

20. The VL domain is (a) X １ IX ２ X ３ TQSPX ４ X ５ LSX ６ SX ７ GX ８ X ９ X １０ X １１ X １２ X １３ FR-L1 comprising the amino acid sequence of X １ is D or E; X ２ is Q or V; X ３ is M or L; X ４ is S or A; X ５ is S or T; X ６ is A or L; X ７ is V, P, or L; X ８ is D or E; X ９ is R or T; X １０ is V or A; X １１ is T or S; X １２ is I or L; X １３ is T, S, or E); (b) WX １ QQKX ２ GX ３ X ４ PX ５ X ６ FR-L2 comprising the amino acid sequence of XLIY (SEQ ID NO: 14) １ is Y or F; X ２ is P or S; X ３ is K or Q; X ４ is S or A; X ５ is K, R, or Q; X ６ is L or S); (c) GX １ PX ２ RFSGSGSGTX ３ FX ４ LX ５ ISX ６ X ７ X ８ PEDX ９ AX １０ YX １１ FR-L3 comprising the amino acid sequence of X (SEQ ID NO: 15) １ is V or I; X ２ is S or A; X ３ is D or R; X ４ is T or S; X ５ is T or K; X ６ is S or G; X ７ is L or M; X ８ is Q or E; X ９ is F, V, or E; X １０ is T, V, or D; X １１ is F or Y; and (d) FGX １ GTKX ２ FR-L4 comprising the amino acid sequence of EIK (SEQ ID NO: 16), １ is G or S, and X ２ is V or L) The antibody of any one of claims 1 to 19, comprising:

21. The VL domain is (a) FR-L1 comprising the amino acid sequence DIQMTQSPSSLSASVGDRVTITC (SEQ ID NO: 21); (b) FR-L2 comprising the amino acid sequence of WYQQKPGKSPKLLIY (SEQ ID NO: 22); (c) FR-L3 comprising the amino acid sequence of GVPSRFSGSGSGTDFTLTISSLQPEDFATYFC (SEQ ID NO: 23); and (d) FR-L4 comprising the amino acid sequence of FGGGTKVEIK (SEQ ID NO: 24) The antibody of any one of claims 1 to 20, comprising:

22. The antibody of any one of claims 1 to 20, wherein the VL domain comprises the amino acid sequence of SEQ ID NO:

8.

23. An isolated antibody, or antigen-binding fragment thereof, that specifically binds to IL-33, wherein the antibody comprises a binding domain comprising (a) a VH domain comprising the amino acid sequence of SEQ ID NO:7 and (b) a VL domain comprising the amino acid sequence of SEQ ID NO:

8.

24. An isolated antibody, or antigen-binding fragment thereof, that specifically binds to IL-33, wherein the antibody comprises a binding domain comprising: (a) a heavy chain (HC) comprising the amino acid sequence of SEQ ID NO:25; and (b) a light chain (LC) comprising the amino acid sequence of SEQ ID NO:

26.

25. The VL domain is (a) FR-L1 comprising the amino acid sequence DIQMTQSPSSLSASVGDRVTITC (SEQ ID NO: 21); (b) FR-L2 comprising the amino acid sequence of WFQQKPGKAPKSLIY (SEQ ID NO: 53); (c) FR-L3 comprising the amino acid sequence of GVPSRFSGSGSGTDFTLTISSLQPEDFATYYC (SEQ ID NO: 54); and (d) FR-L4 comprising the amino acid sequence of FGGGTKVEIK (SEQ ID NO: 24) The antibody of any one of claims 1 to 20, comprising:

26. The antibody of any one of claims 1 to 20, wherein the VL domain comprises the amino acid sequence of SEQ ID NO:

55.

27. The VL domain is (a) FR-L1 comprising the amino acid sequence DIQMTQSPSSLSASVGDRVTITC (SEQ ID NO: 21); (b) FR-L2 comprising the amino acid sequence of WYQQKPGKAPKSLIY (SEQ ID NO: 56); (c) FR-L3 comprising the amino acid sequence of GVPSRFSGSGSGTDFTLTISSLQPEDFATYFC (SEQ ID NO: 23); and (d) FR-L4 comprising the amino acid sequence of FGGGTKVEIK (SEQ ID NO: 24) The antibody of any one of claims 1 to 20, comprising:

28. The antibody of any one of claims 1 to 20, wherein the VL domain comprises the amino acid sequence of SEQ ID NO:

57.

29. The VL domain is (a) FR-L1 comprising the amino acid sequence DIQMTQSPSSLSASVGDRVTITC (SEQ ID NO: 21); (b) FR-L2 comprising the amino acid sequence of WFQQKPGKAPKSLIY (SEQ ID NO: 53); (c) FR-L3 comprising the amino acid sequence of GVPSRFSGSGSGTDFTLTISSLQPEDFATYFC (SEQ ID NO: 23); and (d) FR-L4 comprising the amino acid sequence of FGGGTKVEIK (SEQ ID NO: 24) The antibody of any one of claims 1 to 20, comprising:

30. The antibody of any one of claims 1 to 20, wherein the VL domain comprises the amino acid sequence of SEQ ID NO:

58.

31. The VL domain is (a) FR-L1 comprising the amino acid sequence DIQMTQSPSSLSASVGDRVTITC (SEQ ID NO: 21); (b) FR-L2 comprising the amino acid sequence of WYQQKPGKAPKSLIY (SEQ ID NO: 56); (c) FR-L3 comprising the amino acid sequence of GVPSRFSGSGSGTDFTLTISSLQPEDFATYYC (SEQ ID NO: 54); and (d) FR-L4 comprising the amino acid sequence of FGGGTKVEIK (SEQ ID NO: 24) The antibody of any one of claims 1 to 20, comprising:

32. The antibody of any one of claims 1 to 20, wherein the VL domain comprises the amino acid sequence of SEQ ID NO:

59.

33. The VL domain is (a) FR-L1 comprising the amino acid sequence DIQMTQSPSSLSASVGDRVTITC (SEQ ID NO: 21); (b) FR-L2 comprising the amino acid sequence of WYQQKPGKSPKLLIY (SEQ ID NO: 22); (c) FR-L3 comprising the amino acid sequence of GVPSRFSGSGSGTDFTLTISSLQPEDVATYYC (SEQ ID NO: 60); and (d) FR-L4 comprising the amino acid sequence of FGGGTKVEIK (SEQ ID NO: 24) The antibody of any one of claims 1 to 20, comprising:

34. The antibody of any one of claims 1 to 20, wherein the VL domain comprises the amino acid sequence of SEQ ID NO:

61.

35. An isolated antibody, or antigen-binding fragment thereof, that specifically binds to IL-33, wherein the antibody comprises a binding domain comprising (a) a VH domain comprising the amino acid sequence of SEQ ID NO:41 and (b) a VL domain comprising the amino acid sequence of SEQ ID NO:

55.

36. An isolated antibody, or antigen-binding fragment thereof, that specifically binds to IL-33, wherein the antibody comprises a binding domain comprising (a) a VH domain comprising the amino acid sequence of SEQ ID NO:43 and (b) a VL domain comprising the amino acid sequence of SEQ ID NO:

55.

37. An isolated antibody, or antigen-binding fragment thereof, that specifically binds to IL-33, wherein the antibody comprises a binding domain comprising (a) a VH domain comprising the amino acid sequence of SEQ ID NO:41 and (b) a VL domain comprising the amino acid sequence of SEQ ID NO:

8.

38. An isolated antibody, or antigen-binding fragment thereof, that specifically binds to IL-33, wherein the antibody comprises a binding domain comprising (a) a VH domain comprising the amino acid sequence of SEQ ID NO:43 and (b) a VL domain comprising the amino acid sequence of SEQ ID NO:

8.

39. An isolated antibody, or antigen-binding fragment thereof, that specifically binds to IL-33, wherein the antibody comprises a binding domain comprising (a) a VH domain comprising the amino acid sequence of SEQ ID NO:44 and (b) a VL domain comprising the amino acid sequence of SEQ ID NO:

8.

40. An isolated antibody, or antigen-binding fragment thereof, that specifically binds to IL-33, wherein the antibody comprises a binding domain comprising (a) a VH domain comprising the amino acid sequence of SEQ ID NO:46 and (b) a VL domain comprising the amino acid sequence of SEQ ID NO:

8.

41. An isolated antibody, or antigen-binding fragment thereof, that specifically binds to IL-33, wherein the antibody comprises a binding domain comprising (a) a VH domain comprising the amino acid sequence of SEQ ID NO:48 and (b) a VL domain comprising the amino acid sequence of SEQ ID NO:

8.

42. An isolated antibody, or antigen-binding fragment thereof, that specifically binds to IL-33, wherein the antibody comprises a binding domain comprising (a) a VH domain comprising the amino acid sequence of SEQ ID NO:43 and (b) a VL domain comprising the amino acid sequence of SEQ ID NO:

57.

43. An isolated antibody, or antigen-binding fragment thereof, that specifically binds to IL-33, wherein the antibody comprises a binding domain comprising (a) a VH domain comprising the amino acid sequence of SEQ ID NO:44 and (b) a VL domain comprising the amino acid sequence of SEQ ID NO:

57.

44. An isolated antibody, or antigen-binding fragment thereof, that specifically binds to IL-33, wherein the antibody comprises a binding domain comprising (a) a VH domain comprising the amino acid sequence of SEQ ID NO:46 and (b) a VL domain comprising the amino acid sequence of SEQ ID NO:

57.

45. An isolated antibody, or antigen-binding fragment thereof, that specifically binds to IL-33, wherein the antibody comprises a binding domain comprising (a) a VH domain comprising the amino acid sequence of SEQ ID NO:48 and (b) a VL domain comprising the amino acid sequence of SEQ ID NO:

57.

46. 1. An isolated antibody, or antigen-binding fragment thereof, that specifically binds to IL-33, wherein the antibody comprises a binding domain comprising (a) a VH domain comprising the amino acid sequence of SEQ ID NO:50 and (b) a VL domain comprising the amino acid sequence of SEQ ID NO:

57.

47. An isolated antibody, or antigen-binding fragment thereof, that specifically binds to IL-33, wherein the antibody comprises a binding domain comprising (a) a VH domain comprising the amino acid sequence of SEQ ID NO:43 and (b) a VL domain comprising the amino acid sequence of SEQ ID NO:

58.

48. An isolated antibody, or antigen-binding fragment thereof, that specifically binds to IL-33, wherein the antibody comprises a binding domain comprising (a) a VH domain comprising the amino acid sequence of SEQ ID NO:44 and (b) a VL domain comprising the amino acid sequence of SEQ ID NO:

58.

49. An isolated antibody, or antigen-binding fragment thereof, that specifically binds to IL-33, wherein the antibody comprises a binding domain comprising (a) a VH domain comprising the amino acid sequence of SEQ ID NO:46 and (b) a VL domain comprising the amino acid sequence of SEQ ID NO:

58.

50. An isolated antibody, or antigen-binding fragment thereof, that specifically binds to IL-33, wherein the antibody comprises a binding domain comprising (a) a VH domain comprising the amino acid sequence of SEQ ID NO:48 and (b) a VL domain comprising the amino acid sequence of SEQ ID NO:

58.

51. An isolated antibody, or antigen-binding fragment thereof, that specifically binds to IL-33, wherein the antibody comprises a binding domain comprising (a) a VH domain comprising the amino acid sequence of SEQ ID NO:50 and (b) a VL domain comprising the amino acid sequence of SEQ ID NO:

58.

52. An isolated antibody, or antigen-binding fragment thereof, that specifically binds to IL-33, wherein the antibody comprises a binding domain comprising (a) a VH domain comprising the amino acid sequence of SEQ ID NO:43 and (b) a VL domain comprising the amino acid sequence of SEQ ID NO:

59.

53. An isolated antibody, or antigen-binding fragment thereof, that specifically binds to IL-33, wherein the antibody comprises a binding domain comprising (a) a VH domain comprising the amino acid sequence of SEQ ID NO:44 and (b) a VL domain comprising the amino acid sequence of SEQ ID NO:

59.

54. An isolated antibody, or antigen-binding fragment thereof, that specifically binds to IL-33, wherein the antibody comprises a binding domain comprising (a) a VH domain comprising the amino acid sequence of SEQ ID NO:46 and (b) a VL domain comprising the amino acid sequence of SEQ ID NO:

59.

55. An isolated antibody, or antigen-binding fragment thereof, that specifically binds to IL-33, wherein the antibody comprises a binding domain comprising (a) a VH domain comprising the amino acid sequence of SEQ ID NO:48 and (b) a VL domain comprising the amino acid sequence of SEQ ID NO:

59.

56. An isolated antibody, or antigen-binding fragment thereof, that specifically binds to IL-33, wherein the antibody comprises a binding domain comprising (a) a VH domain comprising the amino acid sequence of SEQ ID NO:50 and (b) a VL domain comprising the amino acid sequence of SEQ ID NO:

59.

57. An isolated antibody, or antigen-binding fragment thereof, that specifically binds to IL-33, wherein the antibody comprises a binding domain comprising (a) a VH domain comprising the amino acid sequence of SEQ ID NO:52 and (b) a VL domain comprising the amino acid sequence of SEQ ID NO:

61.

58. An isolated antibody, or antigen-binding fragment thereof, that specifically binds to IL-33, wherein the antibody comprises: (a) a VH domain comprising an amino acid sequence having at least 95% sequence identity to the amino acid sequence of SEQ ID NO: 35; (b) a VL domain comprising an amino acid sequence having at least 95% sequence identity to the amino acid sequence of SEQ ID NO: 36; or (c) a binding domain comprising the VH domain of (a) and the VL domain of (b).

59. The VH domain is (a) FR-H1 comprising the amino acid sequence of EVQLVESGGGLVQPGTSLKLSCLASGFTFN (SEQ ID NO: 27); (b) FR-H2 comprising the amino acid sequence of WIRQAPGKGLEWIA (SEQ ID NO: 28); (c) FR-H3 comprising the amino acid sequence of RFTISRDDAKSTLYLQMNSLRSEDTATYYCTR (SEQ ID NO: 29); and (d) FR-H4 containing the amino acid sequence WGQGTLVTVSS (SEQ ID NO: 12) 60. The antibody of any one of claims 1, 3, 20, and 58, comprising:

60. The antibody of any one of claims 1, 3, 20, and 58, wherein the VH domain comprises the amino acid sequence of SEQ ID NO:

35.

61. The VL domain is (a) FR-L1 comprising the amino acid sequence DIQMTQSPASLSASLGETVSIEC (SEQ ID NO: 31); (b) FR-L2 comprising the amino acid sequence of WYQQKSGKSPQLLIY (SEQ ID NO: 32); (c) FR-L3 comprising the amino acid sequence of GVPSRFSGSGSGTRFSLKISGMQPEDEADYFC (SEQ ID NO: 33); and (d) FR-L4 comprising the amino acid sequence of FGSGTKLEIK (SEQ ID NO: 34) The antibody of any one of claims 1, 3, 20, and 58-60, comprising:

62. The antibody of any one of claims 1, 3, 20, and 58-60, wherein the VL domain comprises the amino acid sequence of SEQ ID NO:

36.

63. An isolated antibody, or antigen-binding fragment thereof, that specifically binds to IL-33, wherein the antibody comprises a binding domain comprising (a) a VH domain comprising the amino acid sequence of SEQ ID NO: 35 and (b) a VL domain comprising the amino acid sequence of SEQ ID NO:

36.

64. An isolated antibody that specifically binds to IL-33, the antibody comprising a binding domain comprising: (a) a heavy chain (HC) comprising the amino acid sequence of SEQ ID NO: 37; and (b) a light chain (LC) comprising the amino acid sequence of SEQ ID NO:

38.

65. An isolated antibody, or antigen-binding fragment thereof, that specifically binds to IL-33, wherein the antibody comprises: (a) a VH domain comprising an amino acid sequence having at least 95% sequence identity to the amino acid sequence of SEQ ID NO: 65; (b) a VL domain comprising an amino acid sequence having at least 95% sequence identity to the amino acid sequence of SEQ ID NO: 69; or (c) a binding domain comprising the VH domain of (a) and the VL domain of (b).

66. The VH domain is (a) FR-H1 comprising the amino acid sequence of EVQLVQSGAEVKKPGASVKVSCKASGFTFN (SEQ ID NO: 62); (b) FR-H2 comprising the amino acid sequence of WVRQAPGQGLEWMG (SEQ ID NO: 63); (c) FR-H3 comprising the amino acid sequence of RVTMTRDTSTSTTVYMELSSLRSEDTAVYYCTR (SEQ ID NO: 64); and (d) FR-H4 containing the amino acid sequence WGQGTLVTVSS (SEQ ID NO: 12) 66. The antibody of any one of claims 1, 3, 20, and 65, comprising:

67. The antibody of any one of claims 1, 3, 20, and 65, wherein the VH domain comprises the amino acid sequence of SEQ ID NO:

65.

68. The VL domain is (a) FR-L1 comprising the amino acid sequence of EIVLTQSPATTLSLSPGERATLSC (SEQ ID NO: 66); (b) FR-L2 comprising the amino acid sequence of WYQQKPGQAPRLLIY (SEQ ID NO: 67); (c) FR-L3 comprising the amino acid sequence of GIPARFSGSGSGTDFTLTISSLEPEDFAVYYC (SEQ ID NO: 68); and (d) FR-L4 comprising the amino acid sequence of FGGGTKVEIK (SEQ ID NO: 24) 68. The antibody of any one of claims 1, 3, 20, and 65-67, comprising:

69. The antibody of any one of claims 1, 3, 20, and 65-67, wherein the VL domain comprises the amino acid sequence of SEQ ID NO:

69.

70. An isolated antibody, or antigen-binding fragment thereof, that specifically binds to IL-33, wherein the antibody comprises a binding domain comprising (a) a VH domain comprising the amino acid sequence of SEQ ID NO:65 and (b) a VL domain comprising the amino acid sequence of SEQ ID NO:

69.

71. The antibody of any one of claims 1 to 70, wherein the antibody specifically binds to human or cyno IL-33.

72. 72. The antibody of claim 71, wherein the antibody specifically binds to both human and cyno IL-33.

73. The antibody has a K Ｄ 73. The antibody of claim 72, which specifically binds to both human and cyno IL-33.

74. The antibody has a K between about 100 fM and about 1 nM Ｄ The antibody of any one of claims 71 to 73, which specifically binds to human IL-33 at

75. The antibody has a K between about 750 fM and about 300 pM Ｄ The antibody of claim 74, which specifically binds to human IL-33 at

76. The antibody has a K between about 1 pM and about 200 pM Ｄ The antibody of claim 75, which specifically binds to human IL-33 at

77. The antibody has a K Ｄ The antibody of claim 76, which specifically binds to human IL-33 at

78. The antibody has a K Ｄ The antibody of claim 76, which specifically binds to human IL-33 at

79. The antibody has a K between about 100 fM and about 1 nM Ｄ The antibody of any one of claims 71 to 78, which specifically binds to cyno IL-33.

80. The antibody has a K between about 1 pM and about 500 pM Ｄ The antibody of claim 79, which specifically binds to cyno IL-33.

81. The antibody has a K between about 20 pM and about 50 pM Ｄ The antibody of claim 80, which specifically binds to cyno IL-33.

82. The antibody has a K between about 35 pM Ｄ The antibody of claim 81, which specifically binds to cyno IL-33.

83. The antibody has a K between about 1 pM and about 500 pM Ｄ The antibody of claim 72 or 73, which specifically binds to both human and cyno IL-33.

84. The antibody has a K between about 10 pM and about 40 pM Ｄ 84. The antibody of claim 83, which specifically binds to both human and cyno IL-33.

85. The antibody of any one of claims 1 to 84, wherein the antibody is capable of inhibiting the binding of IL-33 to the IL-33 receptor.

86. 86. The antibody of claim 85, wherein the inhibition is measured using a cell-based blocking assay.

87. The antibody of any one of claims 1 to 86, wherein the antibody inhibits the binding of human IL-33 to an IL-33 receptor with an IC50 of between about 800 fM and about 100 pM.

88. The antibody of claim 87, having an IC50 of between about 1 pM and about 50 pM.

89. The antibody of claim 88, having an IC50 of about 31 pM.

90. 90. The antibody of any one of claims 1-89, wherein the antibody has a viscosity of less than about 5 centipoise (cP) at a concentration of about 180 mg / mL.

91. 91. The antibody of claim 90, wherein the antibody has a viscosity of between about 3 cP and about 5 cP at a concentration of about 180 mg / mL.

92. 92. The antibody of claim 91, wherein the antibody has a viscosity of about 4.6 cP at a concentration of about 180 mg / mL.

93. 93. The antibody of any one of claims 1 to 92, wherein the antibody has a turbidity (optical density (OD)) of about 0.5 or less at a concentration of about 150 mg / ml or more in phosphate buffered saline (PBS) pH 7.

4.

94. 94. The antibody of claim 93, wherein the antibody has a turbidity (OD) of between about 0.25 and about 0.5 at a concentration of about 150 mg / ml to about 250 mg / ml.

95. 95. The antibody of claim 94, wherein the antibody has a turbidity (OD) of about 0.38 at a concentration of about 200 mg / ml.

96. The antibody may be monoclonal, human, humanized, or chimeric. An antibody described in any one of claims 1 to 95.

97. The antibody of any one of claims 1 to 96, wherein the antibody is an antibody fragment that binds to IL-33.

98. The antibody fragment is Fab, Fab'-SH, Fv, scFv, or (Fab') ２ 98. The antibody of claim 97, which is a fragment.

99. 99. The antibody of claim 98, wherein the antibody fragment is a Fab.

100. The antibody is a full-length antibody. An antibody described in any one of claims 1 to 96.

101. The antibody of claim 100, wherein the antibody is an IgG antibody.

102. The antibody of claim 101, wherein the IgG antibody is an IgG1 antibody.

103. The antibody of claim 101, wherein the IgG antibody is an IgG4 antibody.

104. The antibody of any one of claims 1 to 103, wherein the antibody is a monospecific antibody.

105. The antibody of any one of claims 1 to 103, wherein the antibody is a multispecific antibody.

106. The antibody of claim 105, wherein the antibody is a bispecific antibody.

107. The antibody of claim 106, wherein the bispecific antibody comprises a second binding domain that binds to a second biological molecule, wherein the second biological molecule is interleukin-13 (IL-13), interleukin-4 (IL-4), interleukin-5 (IL-5), interleukin-17 (IL-17), factor D, HtrA1, VEGF, or a VEGF receptor.

108. An isolated nucleic acid encoding an antibody according to any one of claims 1 to 107, or a set of isolated nucleic acids which together encode said antibody.

109. 109. A vector or set of vectors comprising the isolated nucleic acid or set of isolated nucleic acids of claim 108.

110. 110. A host cell comprising the vector or set of vectors of claim 109.

111. 111. The host cell of claim 110, wherein the host cell is a mammalian cell.

112. 112. The host cell of claim 111, wherein the mammalian cell is a Chinese hamster ovary (CHO) cell.

113. 111. The host cell of claim 110, wherein the host cell is a prokaryotic cell.

114. The host cell of claim 113, wherein the prokaryotic cell is Escherichia coli.

115. A method for producing an antibody that specifically binds to IL-33, comprising culturing the host cell of any one of claims 110 to 114 in a medium.

116. 116. The method of claim 115, wherein the method further comprises recovering the antibody from the host cell or culture medium.

117. A composition comprising an antibody according to any one of claims 1 to 107.

118. 118. The composition of claim 117, further comprising a pharmaceutically acceptable carrier, excipient, or diluent.

119. The composition of claim 118, wherein the composition is a pharmaceutical composition.

120. 120. The composition of claim 119, wherein the pharmaceutical composition further comprises an ST2 binding antagonist, a Factor D binding antagonist, an HtrA1 binding antagonist, a VEGF antagonist, a tryptase-beta binding antagonist, a chemoattractant receptor-like molecule expressed on Th2 cells (CRTH2) binding antagonist, an interleukin-13 (IL-13) binding antagonist, an interleukin-17 (IL-17) binding antagonist, a JAK1 antagonist, and / or an interleukin-5 (IL-5) binding antagonist.

121. The composition of claim 120, wherein the pharmaceutical composition comprises a Factor D binding antagonist.

122. 122. The composition of claim 121, wherein the Factor D binding antagonist is an anti-Factor D antibody or an antigen-binding fragment thereof.

123. The composition of claim 120, wherein the pharmaceutical composition comprises an HtrA1 binding antagonist.

124. The composition of claim 123, wherein the HtrA1 binding antagonist is an anti-HtrA1 antibody or an antigen-binding fragment thereof.

125. The composition of claim 120, wherein the pharmaceutical composition comprises a VEGF antagonist.

126. The composition of claim 125, wherein the VEGF antagonist is an anti-VEGF antibody or an antigen-binding fragment thereof.

127. 127. The composition of any one of claims 117 to 126, wherein the antibody concentration is from about 1 mg / mL to about 400 mg / mL.

128. 128. The composition of claim 127, wherein the antibody concentration is from about 150 mg / mL to about 250 mg / mL.

129. 129. The composition of claim 128, wherein the antibody concentration is from about 175 mg / mL to about 225 mg / mL.

130. 130. The composition of claim 129, wherein the antibody concentration is about 200 mg / mL.

131. An antibody according to any one of claims 1 to 107 or a composition according to any one of claims 119 to 130 for use as a medicament.

132. An antibody according to any one of claims 1 to 107 or a composition according to any one of claims 119 to 130 for use in the treatment of an IL-33 mediated disorder.

133. 133. The antibody or composition for use of claim 132, wherein the IL-33 mediated disorder is an ocular disorder, an inflammatory condition, an immune disorder, a fibrotic disorder, an eosinophilic disorder, an infection, pain, a central nervous system disorder, or a solid tumor.

134. 134. The antibody or composition for use according to claim 133, wherein the ocular disorder is age-related macular degeneration (AMD), ocular retinopathy, polypoidal choroidal vasculopathy (PCV), diabetic macular edema, dry eye disease, Behcet's disease, retinal detachment, glaucoma, uveitis, retinitis pigmentosa, Leber's congenital amaurosis, Stargardt's disease, traumatic eye injury, or conjunctivitis.

135. 135. The antibody or composition for use according to claim 134, wherein the AMD is geographic atrophy (GA), wet AMD or dry AMD.

136. The antibody or composition for use according to claim 135, wherein the AMD is GA.

137. 135. The antibody or composition for use according to claim 134, wherein the AMD is intermediate AMD or advanced AMD.

138. 135. The antibody or composition for use according to claim 134, wherein the ocular retinopathy is diabetic retinopathy (DR) or retinopathy of prematurity (ROP).

139. 135. The antibody or composition for use according to claim 134, wherein the ocular retinopathy is high altitude DR.

140. 135. The antibody or composition for use according to claim 134, wherein the conjunctivitis is infectious or non-infectious conjunctivitis.

141. 135. The antibody or composition for use according to claim 134, wherein the conjunctivitis is allergic conjunctivitis.

142. 134. The antibody or composition for use according to claim 133, wherein the inflammatory condition is asthma, sepsis, septic shock, atopic dermatitis, allergic rhinitis, rheumatoid arthritis, or chronic obstructive pulmonary disease (COPD).

143. 134. The antibody or composition for use according to claim 133, wherein the immune disorder is asthma, rheumatoid arthritis, allergy, anaphylaxis, anaphylactic shock, allergic rhinitis, psoriasis, inflammatory bowel disease (IBD), Crohn's disease, diabetes, or liver disease.

144. 134. The antibody or composition for use according to claim 133, wherein the fibrotic disease is idiopathic pulmonary fibrosis (IPF).

145. 134. The antibody or composition for use according to claim 133, wherein the eosinophilic disorder is eosinophil-associated gastrointestinal disorder (EGID).

146. 146. The antibody or composition for use according to claim 145, wherein the EGID is eosinophilic esophagitis.

147. 134. The antibody or composition for use according to claim 133, wherein the infectious disease is a helminth infection, a protozoan infection, or a viral infection.

148. 148. The antibody or composition for use according to claim 147, wherein the protozoan infection is Leishmania major infection.

149. 148. The antibody or composition for use according to claim 147, wherein the viral infection is a respiratory syncytial virus (RSV) infection or an influenza infection.

150. 134. The antibody or composition for use according to claim 133, wherein the pain is inflammatory pain.

151. 134. The antibody or composition for use according to claim 133, wherein the central nervous system disorder is Alzheimer's disease.

152. 134. The antibody or composition for use according to claim 133, wherein the solid tumor is a breast tumor, a colon tumor, a prostate tumor, a lung tumor, a kidney tumor, a liver tumor, a pancreatic tumor, a stomach tumor, an intestinal tumor, a brain tumor, a bone tumor, and a skin tumor.

153. 153. The antibody or composition for use according to any one of claims 131 to 152, wherein the antibody or composition is used in combination with an ST2 binding antagonist, a Factor D binding antagonist, an HtrA1 binding antagonist, a VEGF antagonist, a tryptase-beta binding antagonist, a CRTH2 binding antagonist, an IL-13 binding antagonist, an IL-17 binding antagonist, a JAK1 antagonist, and / or an IL-5 binding antagonist.

154. 154. The antibody or composition for use according to claim 153, wherein the antibody or composition is used in combination with a Factor D binding antagonist.

155. 155. The antibody or composition for use of claim 154, wherein the Factor D binding antagonist is an anti-Factor D antibody or antigen-binding fragment thereof.

156. 154. The antibody or composition for use according to claim 153, used in combination with an HtrA1 binding antagonist.

157. 157. The antibody or composition for use of claim 156, wherein the HtrA1 binding antagonist is an anti-HtrA1 antibody or an antigen-binding fragment thereof.

158. 154. The antibody or composition for use according to claim 153, used in combination with a VEGF antagonist.

159. 159. The antibody or composition for use of claim 158, wherein the VEGF antagonist is an anti-VEGF antibody or an antigen-binding fragment thereof.

160. Use of an antibody according to any one of claims 1 to 107 or a composition according to any one of claims 119 to 130 in the manufacture of a medicament for the treatment of an IL-33 mediated disorder.

161. 161. The use of claim 160, wherein the IL-33 mediated disorder is an eye disorder, an inflammatory condition, an immune disorder, a fibrotic disorder, an eosinophilic disorder, an infection, pain, a central nervous system disorder, or a solid tumor.

162. 162. The use of claim 161, wherein the eye disorder is AMD, ocular retinopathy, PCV, diabetic macular edema, dry eye disease, Behcet's disease, retinal detachment, glaucoma, uveitis, retinitis pigmentosa, Leber's congenital amaurosis, Stargardt's disease, traumatic eye injury, or conjunctivitis.

163. The use of claim 162, wherein the AMD is GA, wet AMD or dry AMD.

164. The use of claim 163, wherein the AMD is GA.

165. The use of claim 162, wherein the AMD is intermediate AMD or advanced AMD.

166. The use of claim 162, wherein the ocular retinopathy is DR or ROP.

167. The use of claim 162, wherein the ocular retinopathy is high altitude DR.

168. 163. The use of claim 162, wherein the conjunctivitis is infectious or non-infectious conjunctivitis.

169. 163. The use of claim 162, wherein the conjunctivitis is allergic conjunctivitis.

170. 162. The use of claim 161, wherein the inflammatory condition is asthma, sepsis, septic shock, atopic dermatitis, allergic rhinitis, rheumatoid arthritis, or COPD.

171. 162. The use of claim 161, wherein the immune disorder is asthma, rheumatoid arthritis, allergy, anaphylaxis, anaphylactic shock, allergic rhinitis, psoriasis, IBD, Crohn's disease, diabetes, or liver disease.

172. 162. The use of claim 161, wherein the fibrotic disease is IPF.

173. The use of claim 161, wherein the eosinophilic disorder is EGID.

174. The use of claim 173, wherein the EGID is eosinophilic esophagitis.

175. 162. The use of claim 161, wherein the infection is a helminth infection, a protozoan infection, or a viral infection.

176. 176. The use of claim 175, wherein the protozoan infection is Leishmania major infection.

177. 176. The use of claim 175, wherein the viral infection is an RSV infection or an influenza infection.

178. 162. The use of claim 161, wherein the pain is inflammatory pain.

179. 162. The use of claim 161, wherein the central nervous system disorder is Alzheimer's disease.

180. 162. The use of claim 161, wherein the solid tumor is a breast tumor, a colon tumor, a prostate tumor, a lung tumor, a kidney tumor, a liver tumor, a pancreatic tumor, a stomach tumor, an intestinal tumor, a brain tumor, a bone tumor, and a skin tumor.

181. 181. The use of any one of claims 160 to 180, wherein the medicament is formulated for use in combination with an ST2 binding antagonist, a Factor D binding antagonist, an HtrA1 binding antagonist, a VEGF antagonist, a tryptase-beta binding antagonist, a CRTH2 binding antagonist, an IL-13 binding antagonist, an IL-17 binding antagonist, a JAK1 antagonist, and / or an IL-5 binding antagonist.

182. 182. The use of claim 181, wherein the medicament is formulated for use in combination with a Factor D binding antagonist.

183. 183. The use of claim 182, wherein the Factor D binding antagonist is an anti-Factor D antibody or an antigen-binding fragment thereof.

184. 182. The use of claim 181, wherein the medicament is formulated for use in combination with an HtrA1 binding antagonist.

185. The use of claim 184, wherein the HtrA1 binding antagonist is an anti-HtrA1 antibody or an antigen-binding fragment thereof.

186. 182. The use of claim 181, wherein the medicament is formulated for use in combination with a VEGF antagonist.

187. The use of claim 186, wherein the VEGF antagonist is an anti-VEGF antibody or an antigen-binding fragment thereof.

188. 131. A method of treating an IL-33 mediated disorder in a subject in need thereof, comprising administering to the subject a therapeutically effective amount of the antibody of any one of claims 1 to 107 or the composition of any one of claims 119 to 130.

189. 189. The method of claim 188, wherein the IL-33 mediated disorder is an ocular disorder, an inflammatory condition, an immune disorder, a fibrotic disorder, an eosinophilic disorder, an infection, pain, a central nervous system disorder, or a solid tumor.

190. 190. The method of claim 189, wherein the eye disorder is AMD, ocular retinopathy, PCV, diabetic macular edema, dry eye disease, Behcet's disease, retinal detachment, glaucoma, uveitis, retinitis pigmentosa, Leber's congenital amaurosis, Stargardt's disease, traumatic eye injury, or conjunctivitis.

191. 191. The method of claim 190, wherein the AMD is GA, wet AMD, or dry AMD.

192. The method of claim 191, wherein the AMD is GA.

193. 191. The method of claim 190, wherein the AMD is intermediate AMD or advanced AMD.

194. The method of claim 190, wherein the ocular retinopathy is DR or ROP.

195. 191. The method of claim 190, wherein the ocular retinopathy is high altitude DR.

196. 191. The method of claim 190, wherein the conjunctivitis is infectious conjunctivitis or non-infectious conjunctivitis.

197. 191. The method of claim 190, wherein the conjunctivitis is allergic conjunctivitis.

198. 190. The method of claim 189, wherein the inflammatory condition is asthma, sepsis, septic shock, atopic dermatitis, allergic rhinitis, rheumatoid arthritis, or COPD.

199. 190. The method of claim 189, wherein the immune disorder is asthma, rheumatoid arthritis, allergy, anaphylaxis, anaphylactic shock, allergic rhinitis, psoriasis, IBD, Crohn's disease, diabetes, and liver disease.

200. 190. The method of claim 189, wherein the fibrotic disease is IPF.

201. 190. The method of claim 189, wherein the eosinophilic disorder is EGID.

202. The method of claim 201, wherein the EGID is eosinophilic esophagitis.

203. 190. The method of claim 189, wherein the infection is a helminth infection, a protozoan infection, or a viral infection.

204. 204. The method of claim 203, wherein the protozoan infection is Leishmania major infection.

205. 204. The method of claim 203, wherein the viral infection is an RSV infection or an influenza infection.

206. 190. The method of claim 189, wherein the pain is inflammatory pain.

207. 190. The method of claim 189, wherein the solid tumor is a breast tumor, a colon tumor, a prostate tumor, a lung tumor, a kidney tumor, a liver tumor, a pancreatic tumor, a stomach tumor, an intestinal tumor, a brain tumor, a bone tumor, and a skin tumor.

208. 208. The method of any one of claims 188-207, further comprising administering to the subject an ST2 binding antagonist, a Factor D binding antagonist, an HtrA1 binding antagonist, a VEGF antagonist, a tryptase-beta binding antagonist, a CRTH2 binding antagonist, an IL-13 binding antagonist, an IL-17 binding antagonist, a JAK1 antagonist, and / or an IL-5 binding antagonist.

209. 209. The method of claim 208, wherein the method further comprises administering to the subject a Factor D binding antagonist.

210. 210. The method of claim 209, wherein the Factor D binding antagonist is an anti-Factor D antibody or an antigen-binding fragment thereof.

211. 209. The method of claim 208, wherein the method further comprises administering to the subject an HtrA1 binding antagonist.

212. The method of claim 211, wherein the HtrA1 binding antagonist is an anti-HtrA1 antibody or an antigen-binding fragment thereof.

213. 209. The method of claim 208, wherein the method further comprises administering to the subject a VEGF antagonist.

214. The method of claim 213, wherein the VEGF antagonist is an anti-VEGF antibody or an antigen-binding fragment thereof.

215. 108. A method of treating GA in a subject in need thereof, comprising administering to the subject a therapeutically effective amount of an antibody according to any one of claims 1 to 107.

216. The method of claim 215, wherein the antibody is a Fab fragment.

217. 217. The method of any one of claims 188-216, wherein the antibody or composition is administered intravitreally, ophthalmically, intraocularly, juxtasclerally, subtenonally, suprachoroidally, topically, intravenously, intramuscularly, intradermally, transcutaneously, intra-arterially, intraperitoneally, intralesionally, intracranially, intra-articularly, intraprostatically, intrathoracically, intratracheally, intraarachnoidally, intranasally, intravaginally, intrarectally, topically, intratumorally, intraperitoneally, peritoneally, intraventricularly, subcutaneously, subconjunctivally, intravesically, mucosally, intrapericardially, intraumbilically, intraorbitally, orally, transdermally, by inhalation, by injection, by eye drops, by implantation, by infusion, by continuous infusion, by local perfusion bathing directly in target cells, by catheter, by lavage, in a cream, or in a lipid composition.

218. 218. The method of claim 217, wherein the antibody or composition is administered intravitreally, ophthalmically, intraocularly, juxtasclerally, subtenonally, suprachoroidally, or topically.

219. 219. The method of claim 217 or 218, wherein the antibody or composition is administered intravitreally by injection.

220. 219. The method of claim 217 or 218, wherein the antibody or composition is administered topically by eye drops or ointment.

221. 219. The method of claim 217 or 218, wherein the antibody or composition is administered by a port delivery device.

222. The method of any one of claims 188 to 221, wherein the subject is a human.

Images