HK40014665A

HK40014665A - Il-11 antibodies

Info

Publication number: HK40014665A
Application number: HK62020003882.1A
Authority: HK
Inventors: S·A·库克; S·谢弗
Original assignee: 新加坡保健服务集团有限公司; 新加坡国立大学
Priority date: 2016-12-16
Filing date: 2017-12-15
Publication date: 2020-08-21

Description

IL-11 antibodies

Technical Field

The present invention relates to antibodies that bind interleukin 11 (IL-11).

Background

Many fatal and incurable diseases are caused by organ failure due to excessive and maladaptive fibrosis (Rockey et al, 2015 infectious diseases journal 214, jiw 176). Fibrotic diseases include rare genetically driven diseases such as scleroderma, idiopathic pulmonary fibrosis and hypertrophic cardiomyopathy, Dilated Cardiomyopathy (DCM), and common diseases such as atrial fibrillation, ventricular fibrillation, non-alcoholic fatty liver disease, and diabetic nephropathy. Because of the significant impact on morbidity and mortality worldwide, there is a need to develop therapeutic agents that inhibit the fibrotic response (Nanthakumar et al, 2015 Nat Rev Drug Discov14, 693-720).

The main feature of fibrosis is the pathological activation of resident fibroblasts, which drives them from a quiescent state to proliferating, secreting and contracting myofibroblasts (Hinz et al, 2010 Am J Pathology 170, 1807-1816). Stimuli such as mechanical stress and pro-fibrotic cytokines can activate fibroblasts. The TGF β 1 pathway is thought to be critical for the fibrotic response (Leask and Abraham, 2004 FASEB journal 18,816-827), and its inhibitory effect is an ongoing therapeutic strategy (Gourdie et al, 2016 Nature & review & drug discovery 15, 620-638). However, direct inhibition of multifunctional TGF β 1 is associated with serious side effects, such as inflammation and cancer susceptibility.

Summary of The Invention

In one aspect, the invention provides an optionally isolated antibody or antigen-binding fragment capable of binding IL-11, wherein the antibody or antigen-binding fragment is a fully human antibody or antigen-binding fragment and is capable of inhibiting IL-11 trans-signaling.

In another aspect, the invention provides an optionally isolated antibody or antigen-binding fragment capable of binding to IL-11, comprising the amino acid sequences i) to vi):

i)LC-CDR1:X₁X₂DX₃GX₄YX₅Y(SEQ ID NO:239)；

X₆SNX₇GX₈X₉X₁₀(SEQ ID NO:240)；

QX₁₁X₁₂SSX₁₃(SEQ ID NO:241)；

X₁₄GX₁₅IASNX₁₆(SEQ ID NO:242)；

QDVGRY (SEQ ID NO: 101); or

SLRGYY(SEQ ID NO:161)；

ii)LC-CDR2:DVX₁₇(SEQ ID NO:243)；

X₁₈NX₁₉(SEQ ID NO:244)；

X₂₀AS(SEQ ID NO:245)；

X₂₁DX₂₂(SEQ ID NO:246)；

EVX₂₃(SEQ ID NO: 247); or

DX₂₄X₂₅(SEQ ID NO:248)；

iii)LC-CDR3:X₂₆SYTX₂₇X₂₈X₂₉X₃₀X₃₁VX₃₂(SEQ ID NO:249)；

X₃₃SYAX₃₄X₃₅X₃₆X₃₇X₃₈X₃₉X₄₀X₄₁X₄₂X₄₃X₄₄X₄₅X₄₆X₄₇X₄₈X₄₉(SEQ ID NO:250)；

X₅₀X₅₁WDX₅₂X₅₃LX₅₄X₅₅X₅₆V(SEQ ID NO:251)；

QQX₅₇X₅₈X₅₉PX₆₀X₆₁X₆₂X₆₃X₆₄X₆₅X₆₆X₆₇X₆₈X₆₉X₇₀X₇₁X₇₂(SEQ ID NO:252)；

QSYX₇₃X₇₄SX₇₅X₇₆X₇₇X₇₈(SEQ ID NO:253)；

X₇₉SYX₈₀SSX₈₁X₈₂X₈₃VX₈₄(SEQ ID NO:254)；

NSYVTGNNWA (SEQ ID NO: 169); or

DSRGRSGDHWL(SEQ ID NO:163)；

iv)HC-CDR1:GFTFSSYX₈₅(SEQ ID NO:255)；

GX₈₆X₈₇X₈₈X₈₉SYG(SEQ ID NO:256)；

X₉₀X₉₁X₉₂X₉₃X₉₄SYA(SEQ ID NO:257)；

WIFLKSYA(SEQ ID NO:204)；

VSSNSAAWN(SEQ ID NO:180)；

GGSISSSNW (SEQ ID NO: 220); or

GFTFSGAY(SEQ ID NO:183)；

v)HC-CDR2:ISYDGSX₉₅K(SEQ ID NO:258)；

IIPIFGTA(SEQ ID NO:210)；

YRSKWYN(SEQ ID NO:181)；

ISAYGNT (SEQ ID NO: 229); or

IYHSGST(SEQ ID NO:221)；

vi)HC-CDR3:AKLSGPNGVDY(SEQ ID NO:197)；

AKX₉₆X₉₇X₉₈GX₉₉X₁₀₀X₁₀₁X₁₀₂DY(SEQ ID NO:259)；

ARDX₁₀₃GYSSGWYFDY(SEQ ID NO:260)；

ARLX₁₀₄X₁₀₅X₁₀₆X₁₀₇X₁₀₈X₁₀₉X₁₁₀X₁₁₁X₁₁₂X₁₁₃X₁₁₄X₁₁₅X₁₁₆X₁₁₇X₁₁₈X₁₁₉X₁₂₀AFDI(SEQ ID NO:261)；

ARIMGYDYGDYDVVDY(SEQ ID NO:199)；

ARIX₁₂₁X₁₂₂X₁₂₃X₁₂₄X₁₂₅X₁₂₆DX₁₂₇X₁₂₈X₁₂₉X₁₃₀(SEQ ID NO:262)；

ARVGFSSWYPDLYYFDY(SEQ ID NO:205)；

X₁₃₁X₁₃₂X₁₃₃X₁₃₄RGYX₁₃₅DY(SEQ ID NO:263)；

ARITHDYGDFSDAFDI(SEQ ID NO:194)；

ARX₁₃₆GVLX₁₃₇DY(SEQ ID NO:264)；

AKGSYYFDY(SEQ ID NO:235)；

ARLYSGYPSRYYYGMDV(SEQ ID NO:206)；

ARVQSGEPESDY(SEQ ID NO:216)；

AKIGATDPLDY(SEQ ID NO:187)；

ARDLYAFDI(SEQ ID NO:185)；

ARPDDDY(SEQ ID NO:203)；

AKGGKSYYGFDY(SEQ ID NO:207)；

ARADSSAGGGPYYYGMDV(SEQ ID NO:231)；

ARVYYDSSGTQGDSFDY(SEQ ID NO:233)；

ARVVAAARSYYYYMDV(SEQ ID NO:230)；

ARGGGPYYDFWSGYYTEFDY(SEQ ID NO:224)；

ARMVNLYYGDAFDI(SEQ ID NO:218)；

ARGLITGTTP(SEQ ID NO:211)；

ARGQNVDL(SEQ ID NO:198)；

ARVQNLGGGSYYVGAFDY (SEQ ID NO: 222); or

ARLVGATADDY(SEQ ID NO:219)；

Or a variant thereof, wherein one or two or three amino acids of one or more of sequences i) to vi) are substituted with another amino acid;

wherein, X₁Or I, X₂Or R, X₃Either of the two or more of (I) V or I,X₄g, A or N, X₅N, E, K or D, X₆Or Y, X₇Is I or V, X₈Or Y, X₉N, Y or D, X₁₀Is L, Y, T or A, X₁₁G, S or I, X₁₂Is ═ S, I or V, X₁₃Y or N, X₁₄Or T, X₁₅Or N, X₁₆Y or R, X₁₇Or G, X₁₈R, I or G, X₁₉N or D, X₂₀Is A or G, X₂₁Is E, D or N, X₂₂N or D, X₂₃Is ═ S, F or N, X₂₄N or V, X₂₅H or T, X₂₆Or G, X₂₇Or T, X₂₈Or G, X₂₉Is ═ S, N, G or I, X₃₀Either T or S, X₃₁W, L, V or Q, X₃₂Or V, X₃₃Either C or S, X₃₄G or D, X₃₅Is S, Y, N or T, X₃₆Y or N, X₃₇Either T or N, X₃₈W or F, X₃₉Is V, G or L, X₄₀Or V, X₄₁Or R, X₄₂Or R, X₄₃Or R, X₄₄Or D, X₄₅Or R, X₄₆Is absent or A, X₄₇Or D, X₄₈Or R, X₄₉Is absent or P, X₅₀Is A or G, X₅₁Is A or T, X₅₂D, G or S, X₅₃Or G, X₅₄Is S, K or N, X₅₅G or A, X₅₆W, G or H, X₅₇Or Y, X₅₈Y, R or N, X₅₉Or N, X₆₀T, a or W, X₆₁Is L or T, X₆₂Y, A, W or T, X₆₃T, no or F, X₆₄Or G, X₆₅Or G, X₆₆Or G, X₆₇Or T, X₆₈Or K, X₆₉Or V, X₇₀Is absent or E, X₇₁Is absent or F, X₇₂Or K, X₇₃Either D or N, X₇₄Or Y, X₇₅Or K, S or N, X₇₆Or L, X₇₇Is I, V or W, X₇₈Or V, X₇₉Either T or N, X₈₀Either T or S, X₈₁Either T or S, X₈₂P or T, X₈₃Y or L, X₈₄Is absent or A, X₈₅Is A or G, X₈₆F or Y, X₈₇Or T, X₈₈Is L or F, X₈₉G, R, T, S or N, X₉₀G or I, X₉₁G, F or L, X₉₂Or P, X₉₃Is F or S, X₉₄Or D, X₉₅N or D, X₉₆Is L, F or D, X₉₇Y, A or L, X₉₈Or R, X₉₉Is ═ S, V or L, X₁₀₀Is S, Y or P, X₁₀₁Is N, L or I, X₁₀₂Is ═ F or I, X₁₀₃Or V, X₁₀₄H or A, X₁₀₅Is ═ S, Q or F, X₁₀₆Or G, X₁₀₇Is absent or Y, X₁₀₈Or S, X₁₀₉Not, R or S, X₁₁₀Q, N or S, X₁₁₁W or Y, X₁₁₂Or is absent, Y or F, X₁₁₃Is absent or E, X₁₁₄Or W, X₁₁₅Is absent or E, X₁₁₆Is absent or P, X₁₁₇G or S, X₁₁₈Or not, R or T, X₁₁₉G, E or I, X₁₂₀Either D or H, X₁₂₁Is A or G, X₁₂₂Is A or G, X₁₂₃Is A or Y, X₁₂₄Or do not, X₁₂₅G or D, X₁₂₆Is F, M or R, X₁₂₇Is V, Y or A, X₁₂₈Is absent or F, X₁₂₉Or D, X₁₃₀Is absent or I, X₁₃₁Is absent or A, X₁₃₂Or R, X₁₃₃Is A or G, X₁₃₄R or T, X₁₃₅Is F or G, X₁₃₆Or S, X₁₃₇Or F.

In some embodiments, HC-CDR1 is one of VSSNSAAWN (SEQ ID NO:180), GFTFSGAY (SEQ ID NO:183), GFTFSSYG (SEQ ID NO:186), GFTFSSYA (SEQ ID NO:190), GFSFRSYG (SEQ ID NO: 193), GFTFRSYG (SEQ ID NO: 196), GFSFSSYA (SEQ ID NO: 212), WIFLKSYA (SEQ ID NO:204), GFSLNSYG (SEQ ID NO: 217), GGTFSSYA (SEQ ID NO: 209), GGSISSSNW (SEQ ID NO:220), GFSLSSSYG (SEQ ID NO: 201), GGTFSSYA (SEQ ID NO: 209), ILPSDSYA (SEQ ID NO: 226), GYTFTSYG (SEQ ID NO:228), GFTFGSYG (SEQ ID NO:234) or GFSLGSYG (SEQ ID NO: 238).

In some embodiments, HC-CDR2 is one of YRSKWYN (SEQ ID NO:181), ISYDGSNK (SEQ ID NO:184), ISYDGSDK (SEQ ID NO: 188), IIPIFGTA (SEQ ID NO:210), IYHSGST (SEQ ID NO:221), or ISAYGNT (SEQ ID NO: 229).

In some embodiments, HC-CDR3 is ARGTRGYFDY (SEQ ID NO: 182), ARDLYAFDI (SEQ ID NO:185), AKIGATDPLDY (SEQ ID NO:187), AKDLSGLPIIDY (SEQ ID NO: 189), ARRGYFDY (SEQ ID NO: 191), ARIAAADGMDV (SEQ ID NO: 192), ARITHDYGDFSDAFDI (SEQ ID NO:194), AKLYSGSSNFDY (SEQ ID NO: 195), AKLSGPNGVDY (SEQ ID NO:197), ARGQNVDL (SEQ ID NO): 198) ARIMGYDYGDYDVVDY (SEQ ID NO:199) ARRGYGDY (SEQ ID NO: 213) ARVGFSSWYPDLYYFDY (SEQ ID NO:205) AKFARGVYLFDY (SEQ ID NO: 215) ARVQSGEPESDY (SEQ ID NO:216) ARMVNLYYGDAFDI (SEQ ID NO:218) ARLVGATADDY (SEQ ID NO:219) AKLSGPNGVDY (SEQ ID NO:197) ARGLITGTTP (SEQ ID NO:211) ARVQNLGGGSYYVGAFDY (SEQ ID NO:222) ARLHFSQYFSTIDAFDI (SEQ ID NO: 223) ARDVGYSSGWYFDY (SEQ ID NO: 200) ARLAQSYSSSWYEWEPGREHAFDI (SEQ ID NO: 202) ARPDDDY (SEQ ID NO:203) AKLSGPNGVDY (SEQ ID NO:197) ARLYSGYPSRYYYGMDV (SEQ ID NO:206) AKGGKSYYGFDY (SEQ ID NO:207) ARLHSGRNWGDAFDI (SEQ ID NO: 208) ARGGGPYYDFWSGYYTEFDY (SEQ ID NO:224) ARDSGYSSGWYFDY (SEQ ID NO: 225) ARIAAAGRDAFDI (SEQ ID NO: 227) ARVVAAARSYYYYMDV (SEQ ID NO:230) ARADSSAGGGPYYYGMDV (SEQ ID NO:231) ARIGGYDDFDY (SEQ ID NO: 232) ARVYYDSSGTQGDSFDY (SEQ ID NO:233) AKGSYYFDY (SEQ ID NO:235) ARGVLFDY (SEQ ID NO: 236) or argsgvldy (SEQ ID NO:237) one kind of (1).

In some embodiments, LC-CDR1 is one of QDVGRY (SEQ ID NO:101), TGNIASNR (SEQ ID NO:104), SSDVGGYNY (SEQ ID NO:107), SSDVGAYNY (SEQ ID NO:110), SSDIGAYNY (SEQ ID NO:114), SSNIGSNY (SEQ ID NO:116), ISDVGGYNY (SEQ ID NO:122), SSNIGNNL (SEQ ID NO:126), SSDVGGYDY (SEQ ID NO:128), VSSN (SEQ ID NO:137), SSNIGNNY (SEQ ID NO:140), YSNVGSNL (SEQ ID NO:144), SSNIGSNT (SEQ ID NO:147), SRDVGGYNY (SEQ ID NO:150), SGSIASNY (SEQ ID NO:152), ISSY (SEQ ID NO:155), SSDVGGYEY (SEQ ID NO:159), SLRGYY (SEQ ID NO:161), SSNIGSYY (SEQ ID NO:164), SSSIGSYY (SEQ ID NO:167), SSISSY (SEQ ID NO: 82923), SEQ ID NO:175, SEQ ID NO:178, SEQ ID NO:175, SEQ ID NO:178, or SEQ ID NO: 175.

In some embodiments, LC-CDR2 is one of AAS (SEQ ID NO:102), DNH (SEQ ID NO:105), DVS (SEQ ID NO:108), EVS (SEQ ID NO:111), RNN (SEQ ID NO:117), DVT (SEQ ID NO:123), DVH (SEQ ID NO:129), DVG (SEQ ID NO:133), EVN (SEQ ID NO:135), DVT (SEQ ID NO:123), GAS (SEQ ID NO:138), DNT (SEQ ID NO:141), EDD (SEQ ID NO:145), INN (SEQ ID NO:148), DDN (SEQ ID NO:153), EDN (SEQ ID NO:157), GNN (SEQ ID NO:162), RND (SEQ ID NO:165), EVF (SEQ ID NO:168), or NDN (SEQ ID NO: 171).

In some embodiments, LC-CDR3 is QQYRSAPLA (SEQ ID NO:103), QSYDYSSVI (SEQ ID NO:106), SSYTSSSSWV (SEQ ID NO:109), SSYTSSNTLV (SEQ ID NO:112), SSYTSSSTVV (SEQ ID NO:113), SSYTTSSTVV (SEQ ID NO:115), AAWDGSLSGWV (SEQ ID NO:118), SSYTSSSTWV (SEQ ID NO:119), CSYAGSYTFV (SEQ ID NO:120), NSYTSSTPYV (SEQ ID NO:121), SSYAGSYTWV (SEQ ID NO:124), GSYTSSNTQV (SEQ ID NO:125), AAWDDSLSAGV (SEQ ID NO:127), SSYTSSITWV (SEQ ID NO:130), CSYAGSYTWV (SEQ ID NO:131), GSYTSSSTWV (SEQ ID NO:132), SSYTSGSTWV (SEQ ID NO:134), SSYAGTNNFVV (SEQ ID NO:136), QQYNNWPLTFGGGTKVEFK (SEQ ID NO:139), GTWDSSLSGGV (SEQ ID NO:142), SSYAGSYTWGVRRRDRADRP (SEQ ID NO:143), AAWDDSLKGHV (SEQ ID NO:146), AAWDDSLNGWV (SEQ ID NO:149), CSYADYYTWV (SEQ ID NO:151), QSYDSSNLWV (SEQ ID NO:154), QQSYSTPTWT (SEQ ID NO:156), QSYNSSKVV (SEQ ID NO:158), NSYTSSGTLVV (SEQ ID NO:160), DSRGRSGDHWL (SEQ ID NO:163), ATWDDGLSGWV (SEQ ID NO:166), NSYVTGNNWA (SEQ ID NO:169), AAWDDSLSGWV (SEQ ID NO:172), QQSYSTPLYT (SEQ ID NO:174), CSYAGNYTWL (SEQ ID NO:176), TSYSSSSTLVA (SEQ ID NO:177) or SSYTSSSTLVV (SEQ ID NO: 179).

In some embodiments, the antibody or antigen-binding fragment has at least one heavy chain variable region comprising the following CDRs:

HC-CDR1:VSSNSAAWN(SEQ ID NO:180)

HC-CDR2:YRSKWYN(SEQ ID NO:181)

HC-CDR3:ARGTRGYFDY(SEQ ID NO:182)；

or

HC-CDR1:GFTFSGAY(SEQ ID NO:183)

HC-CDR2:ISYDGSNK(SEQ ID NO:184)

HC-CDR3:ARDLYAFDI(SEQ ID NO:185)；

Or

HC-CDR1:GFTFSSYG(SEQ ID NO:186)

HC-CDR2:ISYDGSNK(SEQ ID NO:184)

HC-CDR3:AKIGATDPLDY(SEQ ID NO:187)；

Or

HC-CDR1:GFTFSSYG(SEQ ID NO:186)

HC-CDR2:ISYDGSDK(SEQ ID NO:188)

HC-CDR3:AKDLSGLPIIDY(SEQ ID NO:189)；

Or

HC-CDR1:GFTFSSYA(SEQ ID NO:190)

HC-CDR2:ISYDGSNK(SEQ ID NO:184)

HC-CDR3:ARRGYFDY(SEQ ID NO:191)；

Or

HC-CDR1:GFTFSSYG(SEQ ID NO:186)

HC-CDR2:ISYDGSNK(SEQ ID NO:184)

HC-CDR3:ARIAAADGMDV(SEQ ID NO:192)；

Or

HC-CDR1:GFSFRSYG(SEQ ID NO:193)

HC-CDR2:ISYDGSNK(SEQ ID NO:184)

HC-CDR3:ARITHDYGDFSDAFDI(SEQ ID NO:194)；

Or

HC-CDR1:GFTFSSYG(SEQ ID NO:186)

HC-CDR2:ISYDGSNK(SEQ ID NO:184)

HC-CDR3:AKLYSGSSNFDY(SEQ ID NO:195)；

Or

HC-CDR1:GFTFRSYG(SEQ ID NO:196)

HC-CDR2:ISYDGSNK(SEQ ID NO:184)

HC-CDR3:ARITHDYGDFSDAFDI(SEQ ID NO:194)；

Or

HC-CDR1:GFTFSSYG(SEQ ID NO:186)

HC-CDR2:ISYDGSNK(SEQ ID NO:184)

HC-CDR3:AKLSGPNGVDY(SEQ ID NO:197)；

Or

HC-CDR1:GFTFSSYA(SEQ ID NO:190)

HC-CDR2:ISYDGSNK(SEQ ID NO:184)

HC-CDR3:ARGQNVDL(SEQ ID NO:198)；

Or

HC-CDR1:GFTFSSYA(SEQ ID NO:190)

HC-CDR2:ISYDGSNK(SEQ ID NO:184)

HC-CDR3:ARIMGYDYGDYDVVDY(SEQ ID NO:199)；

Or

HC-CDR1:GFSFSSYA(SEQ ID NO:212)

HC-CDR2:ISYDGSNK(SEQ ID NO:184)

HC-CDR3:ARIMGYDYGDYDVVDY(SEQ ID NO:199)；

Or

HC-CDR1:GFTFSSYG(SEQ ID NO:186)

HC-CDR2:ISYDGSNK(SEQ ID NO:184)

HC-CDR3:ARRGYGDY(SEQ ID NO:213)；

Or

HC-CDR1:WIFLKSYA(SEQ ID NO:204)

HC-CDR2:ISYDGSNK(SEQ ID NO:184)

HC-CDR3:ARVGFSSWYPDLYYFDY(SEQ ID NO:205)；

Or

HC-CDR1:GFTFSSYG(SEQ ID NO:186)

HC-CDR2:ISYDGSNK(SEQ ID NO:184)

HC-CDR3:AKFARGVYLFDY(SEQ ID NO:215)；

Or

HC-CDR1:GFTFSSYA(SEQ ID NO:190)

HC-CDR2:ISYDGSNK(SEQ ID NO:184)

HC-CDR3:ARVQSGEPESDY(SEQ ID NO:216)；

Or

HC-CDR1:GFSLNSYG(SEQ ID NO:217)

HC-CDR2:ISYDGSNK(SEQ ID NO:184)

HC-CDR3:AKLYSGSSNFDY(SEQ ID NO:195)；

Or

HC-CDR1:GFTFSSYA(SEQ ID NO:190)

HC-CDR2:ISYDGSNK(SEQ ID NO:184)

HC-CDR3:ARVGFSSWYPDLYYFDY(SEQ ID NO:205)；

Or

HC-CDR1:GFTFSSYG(SEQ ID NO:186)

HC-CDR2:ISYDGSNK(SEQ ID NO:184)

HC-CDR3:AKLSGPNGVDY(SEQ ID NO:197)；

Or

HC-CDR1:GFTFSSYA(SEQ ID NO:190)

HC-CDR2:ISYDGSNK(SEQ ID NO:184)

HC-CDR3:ARMVNLYYGDAFDI(SEQ ID NO:218)；

Or

HC-CDR1:GFTFSSYA(SEQ ID NO:190)

HC-CDR2:ISYDGSNK(SEQ ID NO:184)

HC-CDR3:ARLVGATADDY(SEQ ID NO:219)；

Or

HC-CDR1:GFTFSSYG(SEQ ID NO:186)

HC-CDR2:ISYDGSNK(SEQ ID NO:184)

HC-CDR3:AKLSGPNGVDY(SEQ ID NO:197)；

Or

HC-CDR1:GGTFSSYA(SEQ ID NO:209)

HC-CDR2:IIPIFGTA(SEQ ID NO:210)

HC-CDR3:ARGLITGTTP(SEQ ID NO:211)；

Or

HC-CDR1:GFTFSSYG(SEQ ID NO:186)

HC-CDR2:ISYDGSNK(SEQ ID NO:184)

HC-CDR3:AKLSGPNGVDY(SEQ ID NO:197)；

Or

HC-CDR1:GGSISSSNW(SEQ ID NO:220)

HC-CDR2:IYHSGST(SEQ ID NO:221)

HC-CDR3:ARVQNLGGGSYYVGAFDY(SEQ ID NO:222)；

Or

HC-CDR1:GFTFSSYG(SEQ ID NO:186)

HC-CDR2:ISYDGSNK(SEQ ID NO:184)

HC-CDR3:ARLHFSQYFSTIDAFDI(SEQ ID NO:223)；

Or

HC-CDR1:GFTFSSYA(SEQ ID NO:190)

HC-CDR2:ISYDGSNK(SEQ ID NO:184)

HC-CDR3:ARIMGYDYGDYDVVDY(SEQ ID NO:199)；

Or

HC-CDR1:GFTFSSYA(SEQ ID NO:190)

HC-CDR2:ISYDGSNK(SEQ ID NO:184)

HC-CDR3:ARDVGYSSGWYFDY(SEQ ID NO:200)；

Or

HC-CDR1:GFSLSSYG(SEQ ID NO:201)

HC-CDR2:ISYDGSNK(SEQ ID NO:184)

HC-CDR3:ARLAQSYSSSWYEWEPGREHAFDI(SEQ ID NO:202)；

Or

HC-CDR1:GFTFSSYA(SEQ ID NO:190)

HC-CDR2:ISYDGSNK(SEQ ID NO:184)

HC-CDR3:ARPDDDY(SEQ ID NO:203)；

Or

HC-CDR1:GFTFSSYG(SEQ ID NO:186)

HC-CDR2:ISYDGSNK(SEQ ID NO:184)

HC-CDR3:AKLSGPNGVDY(SEQ ID NO:197)；

Or

HC-CDR1:WIFLKSYA(SEQ ID NO:204)

HC-CDR2:ISYDGSNK(SEQ ID NO:184)

HC-CDR3:ARVGFSSWYPDLYYFDY(SEQ ID NO:205)；

Or

HC-CDR1:GFTFSSYA(SEQ ID NO:190)

HC-CDR2:ISYDGSNK(SEQ ID NO:184)

HC-CDR3:ARLYSGYPSRYYYGMDV(SEQ ID NO:206)；

Or

HC-CDR1:GFTFSSYG(SEQ ID NO:186)

HC-CDR2:ISYDGSNK(SEQ ID NO:184)

HC-CDR3:AKGGKSYYGFDY(SEQ ID NO:207)；

Or

HC-CDR1:GFTFSSYA(SEQ ID NO:190)

HC-CDR2:ISYDGSNK(SEQ ID NO:184)

HC-CDR3:ARLHSGRNWGDAFDI(SEQ ID NO:208)；

Or

HC-CDR1:GGTFSSYA(SEQ ID NO:209)

HC-CDR2:IIPIFGTA(SEQ ID NO:210)

HC-CDR3: ARGGGPYYDFWSGYYTEFDY (SEQ ID NO: 224); or

HC-CDR1:GFTFSSYA(SEQ ID NO:190)

HC-CDR2:ISYDGSNK(SEQ ID NO:184)

HC-CDR3:ARDSGYSSGWYFDY(SEQ ID NO:225)；

Or

HC-CDR1:GFTFSSYA(SEQ ID NO:190)

HC-CDR2:ISYDGSNK(SEQ ID NO:184)

HC-CDR3:ARDSGYSSGWYFDY(SEQ ID NO:225)；

Or

HC-CDR1:ILPSDSYA(SEQ ID NO:226)

HC-CDR2:ISYDGSNK(SEQ ID NO:184)

HC-CDR3:ARIAAAGRDAFDI(SEQ ID NO:227)；

Or

HC-CDR1:GYTFTSYG(SEQ ID NO:228)

HC-CDR2:ISAYNGNT(SEQ ID NO:229)

HC-CDR3: ARVVAAARSYYYYMDV (SEQ ID NO: 230); or

HC-CDR1:GGTFSSYA(SEQ ID NO:209)

HC-CDR2:IIPIFGTA(SEQ ID NO:210)

HC-CDR3: ARADSSAGGGPYYYGMDV (SEQ ID NO: 231); or

HC-CDR1:GFTFSSYG(SEQ ID NO:186)

HC-CDR2:ISYDGSNK(SEQ ID NO:184)

HC-CDR3:AKFARGVYLFDY(SEQ ID NO:215)；

Or

HC-CDR1:GFTFSSYG(SEQ ID NO:186)

HC-CDR2:ISYDGSNK(SEQ ID NO:184)

HC-CDR3:ARIGGYDDFDY(SEQ ID NO:232)；

Or

HC-CDR1:GFTFSSYA(SEQ ID NO:190)

HC-CDR2:ISYDGSNK(SEQ ID NO:184)

HC-CDR3: ARVYYDSSGTQGDSFDY (SEQ ID NO: 233); or

HC-CDR1:GFTFGSYG(SEQ ID NO:234)

HC-CDR2:ISYDGSNK(SEQ ID NO:184)

HC-CDR3:AKGSYYFDY(SEQ ID NO:235)；

Or

HC-CDR1:GFTFSSYG(SEQ ID NO:186)

HC-CDR2:ISYDGSNK(SEQ ID NO:184)

HC-CDR3:AKLSGPNGVDY(SEQ ID NO:197)；

Or

HC-CDR1:GFSLGSYG(SEQ ID NO:238)

HC-CDR2:ISYDGSNK(SEQ ID NO:184)

HC-CDR3:AKGSYYFDY(SEQ ID NO:235)；

Or

HC-CDR1:GFTFSSYA(SEQ ID NO:190)

HC-CDR2:ISYDGSNK(SEQ ID NO:184)

HC-CDR3:ARGVLFDY(SEQ ID NO:236)；

Or

HC-CDR1:GFTFSSYA(SEQ ID NO:190)

HC-CDR2:ISYDGSNK(SEQ ID NO:184)

HC-CDR3:ARSGVLDY(SEQ ID NO:237).

In some embodiments, the antibody or antigen binding fragment has at least one light chain variable region comprising the following CDRs:

LC-CDR1:QDVGRY(SEQ ID NO:101)

LC-CDR2:AAS(SEQ ID NO:102)

LC-CDR3:QQYRSAPLA(SEQ ID NO:103)；

or

LC-CDR1:TGNIASNR(SEQ ID NO:104)

LC-CDR2:DNH(SEQ ID NO:105)

LC-CDR3:QSYDYSSVI(SEQ ID NO:106)；

Or

LC-CDR1:SSDVGGYNY(SEQ ID NO:107)

LC-CDR2:DVS(SEQ ID NO:108)

LC-CDR3:SSYTSSSSWV(SEQ ID NO:109)；

Or

LC-CDR1:SSDVGAYNY(SEQ ID NO:110)

LC-CDR2:EVS(SEQ ID NO:111)

LC-CDR3:SSYTSSNTLV(SEQ ID NO:112)；

Or

LC-CDR1:SSDVGGYNY(SEQ ID NO:107)

LC-CDR2:DVS(SEQ ID NO:108)

LC-CDR3:SSYTSSSTVV(SEQ ID NO:113)；

Or

LC-CDR1:SSDIGAYNY(SEQ ID NO:114)

LC-CDR2:DVS(SEQ ID NO:108)

LC-CDR3:SSYTTSSTVV(SEQ ID NO:115)；

Or

LC-CDR1:SSNIGSNY(SEQ ID NO:116)

LC-CDR2:RNN(SEQ ID NO:117)

LC-CDR3:AAWDGSLSGWV(SEQ ID NO:118)；

Or

LC-CDR1:SSDVGGYNY(SEQ ID NO:107)

LC-CDR2:DVS(SEQ ID NO:108)

LC-CDR3:SSYTSSSTWV(SEQ ID NO:119)；

Or

LC-CDR1:SSNIGSNY(SEQ ID NO:116)

LC-CDR2:RNN(SEQ ID NO:117)

LC-CDR3:AAWDGSLSGWV(SEQ ID NO:118)；

Or

LC-CDR1:SSDVGGYNY(SEQ ID NO:107)

LC-CDR2:DVS(SEQ ID NO:108)

LC-CDR3:CSYAGSYTFV(SEQ ID NO:120)；

Or

LC-CDR1:SSDVGGYNY(SEQ ID NO:107)

LC-CDR2:DVS(SEQ ID NO:108)

LC-CDR3:NSYTSSTPYV(SEQ ID NO:121)；

Or

LC-CDR1:ISDVGGYNY(SEQ ID NO:122)

LC-CDR2:DVT(SEQ ID NO:123)

LC-CDR3:SSYAGSYTWV(SEQ ID NO:124)；

Or

LC-CDR1:ISDVGGYNY(SEQ ID NO:122)

LC-CDR2:DVT(SEQ ID NO:123)

LC-CDR3:SSYAGSYTWV(SEQ ID NO:124)；

Or

LC-CDR1:SSDVGGYNY(SEQ ID NO:107)

LC-CDR2:DVS(SEQ ID NO:108)

LC-CDR3:GSYTSSNTQV(SEQ ID NO:125)；

Or

LC-CDR1:SSNIGNNL(SEQ ID NO:126)

LC-CDR2:RNN(SEQ ID NO:117)

LC-CDR3:AAWDDSLSAGV(SEQ ID NO:127)；

Or

LC-CDR1:SSDVGGYDY(SEQ ID NO:128)

LC-CDR2:DVH(SEQ ID NO:129)

LC-CDR3:SSYTSSITWV(SEQ ID NO:130)；

Or

LC-CDR1:SSDVGGYNY(SEQ ID NO:107)

LC-CDR2:DVS(SEQ ID NO:108)

LC-CDR3:CSYAGSYTWV(SEQ ID NO:131)；

Or

LC-CDR1:SSDVGGYNY(SEQ ID NO:107)

LC-CDR2:DVS(SEQ ID NO:108)

LC-CDR3:SSYTSSSTWV(SEQ ID NO:119)；

Or

LC-CDR1:SSNIGNNL(SEQ ID NO:126)

LC-CDR2:RNN(SEQ ID NO:117)

LC-CDR3:AAWDDSLSAGV(SEQ ID NO:127)；

Or

LC-CDR1:SSDVGGYNY(SEQ ID NO:107)

LC-CDR2:DVS(SEQ ID NO:108)

LC-CDR3:CSYAGSYTWV(SEQ ID NO:131)；

Or

LC-CDR1:SSDVGGYNY(SEQ ID NO:107)

LC-CDR2:DVS(SEQ ID NO:108)

LC-CDR3:SSYTSSSTVV(SEQ ID NO:113)；

Or

LC-CDR1:SSDVGGYNY(SEQ ID NO:107)

LC-CDR2:DVS(SEQ ID NO:108)

LC-CDR3:GSYTSSSTWV(SEQ ID NO:132)；

Or

LC-CDR1:SSDVGGYNY(SEQ ID NO:107)

LC-CDR2:DVG(SEQ ID NO:133)

LC-CDR3:SSYTSGSTWV(SEQ ID NO:134)；

Or

LC-CDR1:SSDVGGYNY(SEQ ID NO:107)

LC-CDR2:EVN(SEQ ID NO:135)

LC-CDR3:SSYAGTNNFVV(SEQ ID NO:136)；

Or

LC-CDR1:SSDVGGYNY(SEQ ID NO:107)

LC-CDR2:DVT(SEQ ID NO:123)

LC-CDR3:CSYAGSYTWV(SEQ ID NO:131)；

Or

LC-CDR1:QSVSSN(SEQ ID NO:137)

LC-CDR2:GAS(SEQ ID NO:138)

LC-CDR3:QQYNNWPLTFGGGTKVEFK(SEQ ID NO:139)；

Or

LC-CDR1:SSNIGNNY(SEQ ID NO:140)

LC-CDR2:DNT(SEQ ID NO:141)

LC-CDR3:GTWDSSLSGGV(SEQ ID NO:142)；

Or

LC-CDR1:ISDVGGYNY(SEQ ID NO:122)

LC-CDR2:DVT(SEQ ID NO:123)

LC-CDR3:SSYAGSYTWGVRRRDRADRP(SEQ ID NO:143)；

Or

LC-CDR1:YSNVGSNL(SEQ ID NO:144)

LC-CDR2:EDD(SEQ ID NO:145)

LC-CDR3:AAWDDSLKGHV(SEQ ID NO:146)；

Or

LC-CDR1:SSNIGSNT(SEQ ID NO:147)

LC-CDR2:INN(SEQ ID NO:148)

LC-CDR3:AAWDDSLNGWV(SEQ ID NO:149)；

Or

LC-CDR1:SSDVGGYNY(SEQ ID NO:107)

LC-CDR2:DVS(SEQ ID NO:108)

LC-CDR3:CSYAGSYTWV(SEQ ID NO:131)；

Or

LC-CDR1:SRDVGGYNY(SEQ ID NO:150)

LC-CDR2:DVS(SEQ ID NO:108)

LC-CDR3:CSYADYYTWV(SEQ ID NO:151)；

Or

LC-CDR1:SSNIGNNL(SEQ ID NO:126)

LC-CDR2:RNN(SEQ ID NO:117)

LC-CDR3:AAWDDSLSAGV(SEQ ID NO:127)；

Or

LC-CDR1:SGSIASNY(SEQ ID NO:152)

LC-CDR2:DDN(SEQ ID NO:153)

LC-CDR3:QSYDSSNLWV(SEQ ID NO:154)；

Or

LC-CDR1:QIISSY(SEQ ID NO:155)

LC-CDR2:AAS(SEQ ID NO:102)

LC-CDR3:QQSYSTPTWT(SEQ ID NO:156)；

Or

LC-CDR1:SSDVGGYNY(SEQ ID NO:107)

LC-CDR2:DVS(SEQ ID NO:108)

LC-CDR3:SSYTSSSTWV(SEQ ID NO:119)；

Or

LC-CDR1:SGSIASNY(SEQ ID NO:152)

LC-CDR2:EDN(SEQ ID NO:157)

LC-CDR3:QSYNSSKVV(SEQ ID NO:158)；

Or

LC-CDR1:SSDVGGYEY(SEQ ID NO:159)

LC-CDR2:DVS(SEQ ID NO:108)

LC-CDR3:NSYTSSGTLVV(SEQ ID NO:160)；

Or

LC-CDR1:SSDVGGYEY(SEQ ID NO:159)

LC-CDR2:DVS(SEQ ID NO:108)

LC-CDR3:NSYTSSGTLVV(SEQ ID NO:160)；

Or

LC-CDR1:SSDVGGYNY(SEQ ID NO:107)

LC-CDR2:DVS(SEQ ID NO:108)

LC-CDR3:CSYAGSYTWV(SEQ ID NO:131)；

Or

LC-CDR1:SLRGYY(SEQ ID NO:161)

LC-CDR2:GNN(SEQ ID NO:162)

LC-CDR3:DSRGRSGDHWL(SEQ ID NO:163)；

Or

LC-CDR1:SSNIGSYY(SEQ ID NO:164)

LC-CDR2:RND(SEQ ID NO:165)

LC-CDR3:ATWDDGLSGWV(SEQ ID NO:166)；

Or

LC-CDR1:SSDVGAYNY(SEQ ID NO:110)

LC-CDR2:EVF(SEQ ID NO:168)

LC-CDR3:NSYVTGNNWA(SEQ ID NO:169)；

Or

LC-CDR1:SSDVGGYNY(SEQ ID NO:107)

LC-CDR2:DVS(SEQ ID NO:108)

LC-CDR3:SSYTSSSTWV(SEQ ID NO:119)；

Or

LC-CDR1:SSNIGYDA(SEQ ID NO:170)

LC-CDR2:NDN(SEQ ID NO:171)

LC-CDR3:AAWDDSLSGWV(SEQ ID NO:172)；

Or

LC-CDR1:QGSSSY(SEQ ID NO:173)

LC-CDR2:AAS(SEQ ID NO:102)

LC-CDR3:QQSYSTPLYT(SEQ ID NO:174)；

Or

LC-CDR1:SSDVGGYKY(SEQ ID NO:175)

LC-CDR2:DVS(SEQ ID NO:108)

LC-CDR3:CSYAGNYTWL(SEQ ID NO:176)；

Or

LC-CDR1:QGSSSY(SEQ ID NO:173)

LC-CDR2:AAS(SEQ ID NO:102)

LC-CDR3:QQSYSTPLYT(SEQ ID NO:174)；

Or

LC-CDR1:SSDVGGYNY(SEQ ID NO:107)

LC-CDR2:DVS(SEQ ID NO:108)

LC-CDR3:TSYSSSSTLVA(SEQ ID NO:177)；

Or

LC-CDR1:SSDVGNYKY(SEQ ID NO:178)

LC-CDR2:DVS(SEQ ID NO:108)

LC-CDR3:SSYTSSSTLVV(SEQ ID NO:179)。

In another aspect, the invention provides an optionally isolated antibody or antigen-binding fragment capable of binding IL-11, having at least one heavy chain variable region comprising the following CDRs:

HC-CDR1:VSSNSAAWN(SEQ ID NO:180)

HC-CDR2:YRSKWYN(SEQ ID NO:181)

HC-CDR3:ARGTRGYFDY(SEQ ID NO:182)；

or

HC-CDR1:GFTFSGAY(SEQ ID NO:183)

HC-CDR2:ISYDGSNK(SEQ ID NO:184)

HC-CDR3:ARDLYAFDI(SEQ ID NO:185)；

Or

HC-CDR1:GFTFSSYG(SEQ ID NO:186)

HC-CDR2:ISYDGSNK(SEQ ID NO:184)

HC-CDR3:AKIGATDPLDY(SEQ ID NO:187)；

Or

HC-CDR1:GFTFSSYG(SEQ ID NO:186)

HC-CDR2:ISYDGSDK(SEQ ID NO:188)

HC-CDR3:AKDLSGLPIIDY(SEQ ID NO:189)；

Or

HC-CDR1:GFTFSSYA(SEQ ID NO:190)

HC-CDR2:ISYDGSNK(SEQ ID NO:184)

HC-CDR3:ARRGYFDY(SEQ ID NO:191)；

Or

HC-CDR1:GFTFSSYG(SEQ ID NO:186)

HC-CDR2:ISYDGSNK(SEQ ID NO:184)

HC-CDR3:ARIAAADGMDV(SEQ ID NO:192)；

Or

HC-CDR1:GFSFRSYG(SEQ ID NO:193)

HC-CDR2:ISYDGSNK(SEQ ID NO:184)

HC-CDR3: ARITHDYGDFSDAFDI (SEQ ID NO: 194); or

HC-CDR1:GFTFSSYG(SEQ ID NO:186)

HC-CDR2:ISYDGSNK(SEQ ID NO:184)

HC-CDR3:AKLYSGSSNFDY(SEQ ID NO:195)；

Or

HC-CDR1:GFTFRSYG(SEQ ID NO:196)

HC-CDR2:ISYDGSNK(SEQ ID NO:184)

HC-CDR3: ARITHDYGDFSDAFDI (SEQ ID NO: 194); or

HC-CDR1:GFTFSSYG(SEQ ID NO:186)

HC-CDR2:ISYDGSNK(SEQ ID NO:184)

HC-CDR3:AKLSGPNGVDY(SEQ ID NO:197)；

Or

HC-CDR1:GFTFSSYA(SEQ ID NO:190)

HC-CDR2:ISYDGSNK(SEQ ID NO:184)

HC-CDR3:ARGQNVDL(SEQ ID NO:198)；

Or

HC-CDR1:GFTFSSYA(SEQ ID NO:190)

HC-CDR2:ISYDGSNK(SEQ ID NO:184)

HC-CDR3:ARIMGYDYGDYDVVDY(SEQ ID NO:199)；

Or

HC-CDR1:GFSFSSYA(SEQ ID NO:212)

HC-CDR2:ISYDGSNK(SEQ ID NO:184)

HC-CDR3:ARIMGYDYGDYDVVDY(SEQ ID NO:199)；

Or

HC-CDR1:GFTFSSYG(SEQ ID NO:186)

HC-CDR2:ISYDGSNK(SEQ ID NO:184)

HC-CDR3:ARRGYGDY(SEQ ID NO:213)；

Or

HC-CDR1:WIFLKSYA(SEQ ID NO:204)

HC-CDR2:ISYDGSNK(SEQ ID NO:184)

HC-CDR3: ARVGFSSWYPDLYYFDY (SEQ ID NO: 205); or

HC-CDR1:GFTFSSYG(SEQ ID NO:186)

HC-CDR2:ISYDGSNK(SEQ ID NO:184)

HC-CDR3:AKFARGVYLFDY(SEQ ID NO:215)；

Or

HC-CDR1:GFTFSSYA(SEQ ID NO:190)

HC-CDR2:ISYDGSNK(SEQ ID NO:184)

HC-CDR3:ARVQSGEPESDY(SEQ ID NO:216)；

Or

HC-CDR1:GFSLNSYG(SEQ ID NO:217)

HC-CDR2:ISYDGSNK(SEQ ID NO:184)

HC-CDR3:AKLYSGSSNFDY(SEQ ID NO:195)；

Or

HC-CDR1:GFTFSSYA(SEQ ID NO:190)

HC-CDR2:ISYDGSNK(SEQ ID NO:184)

HC-CDR3:ARVGFSSWYPDLYYFDY(SEQ ID NO:205)；

Or

HC-CDR1:GFTFSSYG(SEQ ID NO:186)

HC-CDR2:ISYDGSNK(SEQ ID NO:184)

HC-CDR3:AKLSGPNGVDY(SEQ ID NO:197)；

Or

HC-CDR1:GFTFSSYA(SEQ ID NO:190)

HC-CDR2:ISYDGSNK(SEQ ID NO:184)

HC-CDR3:ARMVNLYYGDAFDI(SEQ ID NO:218)；

Or

HC-CDR1:GFTFSSYA(SEQ ID NO:190)

HC-CDR2:ISYDGSNK(SEQ ID NO:184)

HC-CDR3:ARLVGATADDY(SEQ ID NO:219)；

Or

HC-CDR1:GFTFSSYG(SEQ ID NO:186)

HC-CDR2:ISYDGSNK(SEQ ID NO:184)

HC-CDR3:AKLSGPNGVDY(SEQ ID NO:197)；

Or

HC-CDR1:GGTFSSYA(SEQ ID NO:209)

HC-CDR2:IIPIFGTA(SEQ ID NO:210)

HC-CDR3:ARGLITGTTP(SEQ ID NO:211)；

Or

HC-CDR1:GFTFSSYG(SEQ ID NO:186)

HC-CDR2:ISYDGSNK(SEQ ID NO:184)

HC-CDR3:AKLSGPNGVDY(SEQ ID NO:197)；

Or

HC-CDR1:GGSISSSNW(SEQ ID NO:220)

HC-CDR2:IYHSGST(SEQ ID NO:221)

HC-CDR3:ARVQNLGGGSYYVGAFDY(SEQ ID NO:222)；

Or

HC-CDR1:GFTFSSYG(SEQ ID NO:186)

HC-CDR2:ISYDGSNK(SEQ ID NO:184)

HC-CDR3:ARLHFSQYFSTIDAFDI(SEQ ID NO:223)；

Or

HC-CDR1:GFTFSSYA(SEQ ID NO:190)

HC-CDR2:ISYDGSNK(SEQ ID NO:184)

HC-CDR3:ARIMGYDYGDYDVVDY(SEQ ID NO:199)；

Or

HC-CDR1:GFTFSSYA(SEQ ID NO:190)

HC-CDR2:ISYDGSNK(SEQ ID NO:184)

HC-CDR3:ARDVGYSSGWYFDY(SEQ ID NO:200)；

Or

HC-CDR1:GFSLSSYG(SEQ ID NO:201)

HC-CDR2:ISYDGSNK(SEQ ID NO:184)

HC-CDR3:ARLAQSYSSSWYEWEPGREHAFDI(SEQ ID NO:202)；

Or

HC-CDR1:GFTFSSYA(SEQ ID NO:190)

HC-CDR2:ISYDGSNK(SEQ ID NO:184)

HC-CDR3:ARPDDDY(SEQ ID NO:203)；

Or

HC-CDR1:GFTFSSYG(SEQ ID NO:186)

HC-CDR2:ISYDGSNK(SEQ ID NO:184)

HC-CDR3:AKLSGPNGVDY(SEQ ID NO:197)；

Or

HC-CDR1:WIFLKSYA(SEQ ID NO:204)

HC-CDR2:ISYDGSNK(SEQ ID NO:184)

HC-CDR3:ARVGFSSWYPDLYYFDY(SEQ ID NO:205)；

Or

HC-CDR1:GFTFSSYA(SEQ ID NO:190)

HC-CDR2:ISYDGSNK(SEQ ID NO:184)

HC-CDR3:ARLYSGYPSRYYYGMDV(SEQ ID NO:206)；

Or

HC-CDR1:GFTFSSYG(SEQ ID NO:186)

HC-CDR2:ISYDGSNK(SEQ ID NO:184)

HC-CDR3:AKGGKSYYGFDY(SEQ ID NO:207)；

Or

HC-CDR1:GFTFSSYA(SEQ ID NO:190)

HC-CDR2:ISYDGSNK(SEQ ID NO:184)

HC-CDR3:ARLHSGRNWGDAFDI(SEQ ID NO:208)；

Or

HC-CDR1:GGTFSSYA(SEQ ID NO:209)

HC-CDR2:IIPIFGTA(SEQ ID NO:210)

HC-CDR3: ARGGGPYYDFWSGYYTEFDY (SEQ ID NO: 224); or

HC-CDR1:GFTFSSYA(SEQ ID NO:190)

HC-CDR2:ISYDGSNK(SEQ ID NO:184)

HC-CDR3:ARDSGYSSGWYFDY(SEQ ID NO:225)；

Or

HC-CDR1:GFTFSSYA(SEQ ID NO:190)

HC-CDR2:ISYDGSNK(SEQ ID NO:184)

HC-CDR3:ARDSGYSSGWYFDY(SEQ ID NO:225)；

Or

HC-CDR1:ILPSDSYA(SEQ ID NO:226)

HC-CDR2:ISYDGSNK(SEQ ID NO:184)

HC-CDR3:ARIAAAGRDAFDI(SEQ ID NO:227)；

Or

HC-CDR1:GYTFTSYG(SEQ ID NO:228)

HC-CDR2:ISAYNGNT(SEQ ID NO:229)

HC-CDR3:ARVVAAARSYYYYMDV(SEQ ID NO:230)；

Or

HC-CDR1:GGTFSSYA(SEQ ID NO:209)

HC-CDR2:IIPIFGTA(SEQ ID NO:210)

HC-CDR3:ARADSSAGGGPYYYGMDV(SEQ ID NO:231)；

Or

HC-CDR1:GFTFSSYG(SEQ ID NO:186)

HC-CDR2:ISYDGSNK(SEQ ID NO:184)

HC-CDR3:AKFARGVYLFDY(SEQ ID NO:215)；

Or

HC-CDR1:GFTFSSYG(SEQ ID NO:186)

HC-CDR2:ISYDGSNK(SEQ ID NO:184)

HC-CDR3:ARIGGYDDFDY(SEQ ID NO:232)；

Or

HC-CDR1:GFTFSSYA(SEQ ID NO:190)

HC-CDR2:ISYDGSNK(SEQ ID NO:184)

HC-CDR3:ARVYYDSSGTQGDSFDY(SEQ ID NO:233)；

Or

HC-CDR1:GFTFGSYG(SEQ ID NO:234)

HC-CDR2:ISYDGSNK(SEQ ID NO:184)

HC-CDR3:AKGSYYFDY(SEQ ID NO:235)；

Or

HC-CDR1:GFTFSSYG(SEQ ID NO:186)

HC-CDR2:ISYDGSNK(SEQ ID NO:184)

HC-CDR3:AKLSGPNGVDY(SEQ ID NO:197)；

Or

HC-CDR1:GFSLGSYG(SEQ ID NO:238)

HC-CDR2:ISYDGSNK(SEQ ID NO:184)

HC-CDR3:AKGSYYFDY(SEQ ID NO:235)；

Or

HC-CDR1:GFTFSSYA(SEQ ID NO:190)

HC-CDR2:ISYDGSNK(SEQ ID NO:184)

HC-CDR3:ARGVLFDY(SEQ ID NO:236)；

Or

HC-CDR1:GFTFSSYA(SEQ ID NO:190)

HC-CDR2:ISYDGSNK(SEQ ID NO:184)

HC-CDR3 ARSGVLDY (SEQ ID NO: 237); and

with at least one light chain variable region for subsequent light chain substitutions.

In another aspect, the invention provides an optionally isolated antibody or antigen-binding fragment capable of binding IL-11, comprising light and heavy chain variable region sequences, wherein:

the light chain includes LC-CDR1, LC-CDR2, LC-CDR3 having at least 85% overall sequence identity to LC-CDR1, LC-CDR1: x₁X₂DX₃GX₄YX₅Y(SEQ ID NO:239)，X₆SNX₇GX₈X₉X₁₀(SEQ ID NO:240),QX₁₁X₁₂SSX₁₃(SEQ ID NO:241),X₁₄GX₁₅IASNX₁₆(SEQ ID NO:242), QDVGRY (SEQ ID NO:101), or SLRGYY (SEQ ID NO: 161); LC-CDR 2: DVX₁₇(SEQ ID NO:243),X₁₈NX₁₉(SEQ ID NO:244),X₂₀AS(SEQ ID NO:245),X₂₁DX₂₂(SEQ ID NO:246),EVX₂₃(SEQ ID NO:247), or DX₂₄X₂₅(SEQ ID NO: 248); LC-CDR 3: x₂₆SYTX₂₇X₂₈X₂₉X₃₀X₃₁VX₃₂(SEQ ID NO:249),X₃₃SYAX₃₄X₃ ₅X₃₆X₃₇X₃₈X₃₉X₄₀X₄₁X₄₂X₄₃X₄₄X₄₅X₄₆X₄₇X₄₈X₄₉(SEQ ID NO:250),X₅₀X₅₁WDX₅₂X₅₃LX₅₄X₅₅X₅₆V(SEQ ID NO:251),QQX₅₇X₅₈X₅₉PX₆₀X₆₁X₆₂X₆₃X₆₄X₆₅X₆₆X₆₇X₆₈X₆₉X₇₀X₇₁X₇₂(SEQ ID NO:252),QSYX₇₃X₇₄SX₇₅X₇₆X₇₇X₇₈(SEQ ID NO:253),X₇₉SYX₈₀SSX₈₁X₈₂X₈₃VX₈₄(SEQ ID NO:254), NSYVTGNNWA (SEQ ID NO:169), or DSRGRSGDHWL (SEQ ID NO: 163); and

the heavy chain includes HC-CDR1, HC-CDR2, HC-CDR3, which has at least 85% overall sequence identity with HC-CDR1, HC-CDR 1: GFTFSSYX₈₅(SEQ ID NO:255),GX₈₆X₈₇X₈₈X₈₉SYG(SEQ ID NO:256),X₉₀X₉₁X₉₂X₉₃X₉₄One of SYA (SEQ ID NO:257), WIFLKSYA (SEQ ID NO:204), VSSNSAAWN (SEQ ID NO:180), GGSISSSNW (SEQ ID NO:220), or GFTFSGAY (SEQ ID NO:183)；HC-CDR2：ISYDGSX₉₅K (SEQ ID NO:258), IIPIFGTA (SEQ ID NO:210), YRSKWYN (SEQ ID NO:181), ISAYGNT (SEQ ID NO:229), or IYHSGST (SEQ ID NO: 221); HC-CDR3: AKLSGPNGVDY (SEQ ID NO:197), AKX₉₆X₉₇X₉₈GX₉₉X₁₀₀X₁₀₁X₁₀₂DY(SEQ ID NO:259),ARDX₁₀₃GYSSGWYFDY(SEQ ID NO:260),ARLX₁₀₄X₁₀₅X₁₀₆X₁₀₇X₁₀₈X₁₀₉X₁₁₀X₁₁₁X₁₁₂X₁₁₃X₁₁₄X₁₁₅X₁₁₆X₁₁₇X₁₁₈X₁₁₉X₁₂₀AFDI(SEQ ID NO:261),ARIMGYDYGDYDVVDY(SEQ ID NO:199),ARIX₁₂₁X₁₂₂X₁₂₃X₁₂₄X₁₂₅X₁₂₆DX₁₂₇X₁₂₈X₁₂₉X₁₃₀(SEQ ID NO:262),ARVGFSSWYPDLYYFDY(SEQ ID NO:205),X₁₃₁X₁₃₂X₁₃₃X₁₃₄RGYX₁₃₅DY(SEQ ID NO:263),ARITHDYGDFSDAFDI(SEQ ID NO:194),ARX₁₃₆GVLX₁₃₇DY (SEQ ID NO:264), AKGSYYFDY (SEQ ID NO:235), ARLYSGYPSRYYYGMDV (SEQ ID NO:206), ARVQSGEPESDY (SEQ ID NO:216), AKIGATDPLDY (SEQ ID NO:187), ARDLYAFDI (SEQ ID NO:185), ARPDDDY (SEQ ID NO:203), AKGGKSYYGFDY (SEQ ID NO:207), ARADSSAGGGPYYYGMDV (SEQ ID NO:231), ARVYYDSSGTQGDSFDY (SEQ ID NO:233), ARVVAAARSYYYYMDV (SEQ ID NO:230), ARGGGPYYDFWSGYYTEFDY (SEQ ID NO:224), ARMVNLYYGDAFDI (SEQ ID NO:218), ARGLITGTTP (SEQ ID NO:211), ARGQNVDL (SEQ ID NO:198), ARVQNLGGGSYYVGAFDY (SEQ ID NO:222), or ARLVGATADDY (SEQ ID NO: 219);

wherein X₁Or I, X₂Or R, X₃Either V or I, X₄G, A or N, X₅N, E, K or D, X₆Or Y, X₇Is I or V, X₈Or Y, X₉N, Y or D, X₁₀Is L, Y, T or A, X₁₁G, S or I, X₁₂Is ═ S, I or V, X₁₃Y or N, X₁₄Or T, X₁₅Or N, X₁₆Y or R, X₁₇Or G, X₁₈R, I or G, X₁₉N or D, X₂₀Is A or G, X₂₁Is E, D or N, X₂₂N or D, X₂₃Is ═ S, F or N, X₂₄N or V, X₂₅H or T, X₂₆Or G, X₂₇Or T, X₂₈Or G, X₂₉Is ═ S, N, G or I, X₃₀Either T or S, X₃₁W, L, V or Q, X₃₂Or V, X₃₃Either C or S, X₃₄G or D, X₃₅Is S, Y, N or T, X₃₆Y or N, X₃₇Either T or N, X₃₈W or F, X₃₉Is V, G or L, X₄₀Or V, X₄₁Or R, X₄₂Or R, X₄₃Or R, X₄₄Or D, X₄₅Or R, X₄₆Is absent or A, X₄₇Or D, X₄₈Or R, X₄₉Is absent or P, X₅₀Is A or G, X₅₁Is A or T, X₅₂D, G or S, X₅₃Or G, X₅₄Is S, K or N, X₅₅G or A, X₅₆W, G or H, X₅₇Or Y, X₅₈Y, R or N, X₅₉Or N, X₆₀T, a or W, X₆₁Is L or T, X₆₂Y, A, W or T, X₆₃T, no or F, X₆₄Or G, X₆₅Or G, X₆₆Or G, X₆₇Or T, X₆₈Or K, X₆₉Or V, X₇₀Is absent or E, X₇₁Is absent or F, X₇₂Or K, X₇₃Either D or N, X₇₄Or Y, X₇₅Or K, S or N, X₇₆Or L, X₇₇Is I, V or W, X₇₈Or V, X₇₉Either T or N, X₈₀Either T or S, X₈₁Either T or S, X₈₂P or T, X₈₃Y or L, X₈₄Is absent or A, X₈₅Is A or G, X₈₆F or Y, X₈₇Or T, X₈₈Is L or F, X₈₉G, R, T, S or N, X₉₀G or I, X₉₁G, F or L, X₉₂Or P, X₉₃Is F or S, X₉₄Or D, X₉₅N or D, X₉₆Is L, F or D, X₉₇Y, A or L, X₉₈Or R, X₉₉Is ═ S, V or L, X₁₀₀Is S, Y or P, X₁₀₁Is N, L or I, X₁₀₂Is ═ F or I, X₁₀₃Or V, X₁₀₄H or A, X₁₀₅Is ═ S, Q or F, X₁₀₆Or G, X₁₀₇Is absent or Y, X₁₀₈Or S, X₁₀₉Not, R or S, X₁₁₀Q, N or S, X₁₁₁W or Y, X₁₁₂Or is absent, Y or F, X₁₁₃Is absent or E, X₁₁₄Or W, X₁₁₅Is absent or E, X₁₁₆Is absent or P, X₁₁₇G or S, X₁₁₈Or not, R or T, X₁₁₉G, E or I, X₁₂₀Either D or H, X₁₂₁Is A or G, X₁₂₂Is A or G, X₁₂₃Is A or Y, X₁₂₄Or do not, X₁₂₅G or D, X₁₂₆Is F, M or R, X₁₂₇Is V, Y or A, X₁₂₈Is absent or F, X₁₂₉Or D, X₁₃₀Is absent or I, X₁₃₁Is absent or A, X₁₃₂Or R, X₁₃₃Is A or G, X₁₃₄R or T, X₁₃₅Is F or G, X₁₃₆Or S, X₁₃₇Or F.

the light chain sequence is similar to SEQ ID NO:1 to 50 has at least 85% sequence identity to the light chain sequence; and

the heavy chain sequence is similar to SEQ ID NO: the heavy chain sequence of one of 51 to 100 has at least 85% sequence identity.

In another aspect, the invention provides an optionally isolated antibody or antigen-binding fragment capable of binding IL-11, which is capable of inhibiting IL-11 trans-signaling, optionally wherein the antibody or antigen-binding fragment is an antibody or antigen-binding fragment described herein.

In some embodiments of the various aspects of the invention, the antibody or antigen binding fragment is conjugated to a drug moiety or detectable moiety.

In another aspect, the invention provides a complex, optionally in vitro, and/or optionally isolated, comprising an antibody or antigen-binding fragment of the invention that binds to IL-11.

In another aspect, the invention provides a composition comprising an antibody or antigen-binding fragment of the invention, and at least one pharmaceutically acceptable carrier.

In another aspect, the invention provides an isolated nucleic acid encoding an antibody or antigen-binding fragment of the invention.

In some embodiments, the nucleic acid comprises a nucleotide sequence identical to SEQ ID NO: 476 to 539, or an equivalent sequence due to codon degeneracy, having at least 60%, 70%, 80%, 90%, 95% or more sequence identity. In some embodiments, the nucleic acid comprises a nucleotide sequence identical to SEQ ID NO: 571 to 580, or an equivalent sequence due to codon degeneracy, with a sequence identity of at least 60%, 70%, 80%, 90%, 95% or more.

In another aspect, the invention provides a vector comprising a nucleic acid according to the invention.

In another aspect, the invention provides a host cell comprising a vector of the invention.

In another aspect, the invention provides a method of making an antibody or antigen-binding fragment of the invention, comprising culturing a host cell of the invention under conditions suitable for expression of the antibody or antigen-binding fragment, and recovering the antibody or antigen-binding fragment.

In another aspect, the invention provides the use of an antibody, antigen-binding fragment or composition of the invention in a method of therapy or medical treatment.

In another aspect, the invention provides the use of an antibody, antigen-binding fragment or composition of the invention in the treatment or prevention of fibrosis, or a disease/disorder characterized by fibrosis.

In another aspect, the invention provides the use of an antibody, antigen-binding fragment or composition of the invention in the treatment of cancer.

In another aspect, the invention provides the use of an antibody, antigen-binding fragment or composition of the invention in the manufacture of a medicament for the treatment or prevention of fibrosis or a disease/disorder characterized by fibrosis.

In another aspect, the invention provides the use of an antibody, antigen-binding fragment or composition of the invention in the manufacture of a medicament for the treatment or prevention of cancer.

In another aspect, the invention provides a method of treating fibrosis comprising administering to an individual having fibrosis or a disease/disorder characterized by fibrosis an antibody, antigen-binding fragment or composition of the invention.

In another aspect, the invention provides a method of treating cancer comprising administering to an individual having cancer an antibody, antigen-binding fragment, or composition of the invention.

In another aspect, the invention provides an antibody or antigen-binding fragment for use in a method of treating a disease, wherein IL-11 mediated signaling is associated with a pathology of the disease, wherein the antibody or antigen-binding fragment is capable of inhibiting IL-11 trans signaling.

In another aspect, the invention provides the use of an antibody or antigen-binding fragment in the manufacture of a medicament for treating a disease in which IL-11 mediated signaling is implicated in the pathology of the disease, wherein the antibody or antigen-binding fragment is capable of inhibiting IL-11 trans-signaling.

In another aspect, the invention provides a method of treating a disease in which IL-11 mediated signaling is associated with the pathology of the disease, comprising administering to an individual having the disease an antibody or antigen-binding fragment, wherein the antibody or antigen-binding fragment is capable of inhibiting IL-11 trans-signaling.

In another aspect, the invention provides a method comprising contacting a sample containing or suspected of containing IL-11 with an antibody or antigen-binding fragment of the invention and detecting the formation of a complex of the antibody or antigen-binding fragment and IL-11.

In another aspect, the invention provides a method of diagnosing a disease or disorder in an individual, the method comprising contacting a sample from the individual with an antibody or antigen-binding fragment of the invention in vitro and detecting the formation of a complex of the antibody or antigen-binding fragment and IL-11.

In another aspect, the invention provides a method of selecting or stratifying an individual for treatment with an IL-11-targeting agent, the method comprising contacting a sample from the individual in vitro with an antibody or antigen-binding fragment of the invention and detecting the formation of a complex of the antibody or antigen-binding fragment and IL-11.

In another aspect, the invention provides the use of an antibody or antigen-binding fragment of the invention to detect IL-11 in vitro or in vivo.

In another aspect, the invention provides the use of an antibody or antigen-binding fragment of the invention as a diagnostic or prognostic agent, in vitro or in vivo.

In another aspect, the invention provides an optionally isolated antibody or antigen-binding fragment capable of binding to IL-11, comprising the amino acid sequences of sequences i) to vi):

i)LC-CDR1:X₁₃₈X₁₃₉DVGGYX₁₄₀X₁₄₁(SEQ ID NO:393),SSDVX₁₄₂X₁₄₃YX₁₄₄Y(SEQ ID NO:394),X₁₄₅X₁₄₆DX₁₄₇GAYNY(SEQ ID NO:395),SSDIGX₁₄₈YNY(SEQ ID NO:396),X₁₄₉SDVGAYDY(SEQ ID NO:397),SGDVGTYX₁₅₀Y(SEQ ID NO:398),QX₁₅₁IX₁₅₂SY(SEQ ID NO:399),QSX₁₅₃SSSY(SEQ ID NO:400),RX₁₅₄DX₁₅₅GGYDX₁₅₆(SEQ ID NO:401), SSNVGGYNY (SEQ ID NO:284), GSNVGGYNY (SEQ ID NO:349) or QSVNSAY (SEQ ID NO: 359);

ii)LC-CDR2:DVX₁₅₇(SEQ ID NO:402) or X₁₅₈AS(SEQ ID NO:403)；

iii)LC-CDR3:X₁₅₉SYAGX₁₆₀X₁₆₁X₁₆₂WX₁₆₃(SEQ ID NO:404),SSYTX₁₆₄X₁₆₅X₁₆₆X₁₆₇WV(SEQ ID NO:405),QQSYSX₁₆₈PX₁₆₉WT(SEQ ID NO:406),SSFX₁₇₀X₁₇₁SX₁₇₂X₁₇₃WV (SEQ ID NO:407), NSYTSGSTWV (SEQ ID NO:362), ASYTRSSVWV (SEQ ID NO:334), QQSSTSPTWA (SEQ ID NO:357), or SSYRSGSTLGVRRRDQADRPR (SEQ ID NO: 282);

iv)HC-CDR1:GFTFX₁₇₄SYX₁₇₅(SEQ ID NO:409)；

v)HC-CDR2:ISYDGSNX₁₇₆(SEQ ID NO:410)；

vi) HC-CDR3: AKIGATDPLDY (SEQ ID NO:187), ARIMGYDYGDYDVVDY (SEQ ID NO:199), AKLSGPNGVDY (SEQ ID NO:197) or AKGX₁₇₇X₁₇₈SYYX₁₇₉FDY(SEQ ID NO:411)；

Or a variant thereof, wherein one or more of the sequences i) to vi) has one or two or three amino acids substituted by another amino acid;

wherein X₁₃₈Is ═ S, N or I, X₁₃₉Or R, X₁₄₀N, E or D, X₁₄₁Y or F, X₁₄₂G or A, X₁₄₃D, G or T, X₁₄₄N or D, X₁₄₅Or N, X₁₄₆N, T or S, X₁₄₇Either V or I, X₁₄₈Either V or G, X₁₄₉Or G, X₁₅₀N or D, X₁₅₁Is A or I, X₁₅₂N or S, X₁₅₃Is F or V, X₁₅₄Or R, X₁₅₅Is I or V, X₁₅₆Y or F, X₁₅₇Is S, T, N, G, V or D, X₁₅₈Is A or G, X₁₅₉Is C, S, A or N, X₁₆₀Is S, R, N, G, T or F, X₁₆₁Y or H, X₁₆₂Is T, N, I, S or V, X₁₆₃Is V, M or I, X₁₆₄Or N, X₁₆₅Or N, X₁₆₆Is T, I, S or R, X₁₆₇Either T or S, X₁₆₈Either T or D, X₁₆₉Or T, X₁₇₀Either T or A, X₁₇₁Either T or S, X₁₇₂Is I or T, X₁₇₃Is A or T, X₁₇₄Or G, X₁₇₅G or A, X₁₇₆Or R, X₁₇₇Or G, X₁₇₈Or K, and X₁₇₉Or G.

In some embodiments, HC-CDR1 is one of GFTFSSYG (SEQ ID NO:186), GFTFSSYA (SEQ ID NO:190) or GFTFGSYG (SEQ ID NO: 234).

In some embodiments, HC-CDR2 is one of ISYDGSNK (SEQ ID NO:184) or ISYDGSNR (SEQ ID NO: 381).

In some embodiments, HC-CDR3 is one of AKIGATDPLDY (SEQ ID NO:187), ARIMGYDYGDYDVVDY (SEQ ID NO:199), AKGGKSYYGFDY (SEQ ID NO:207), AKGSYYFDY (SEQ ID NO:235) or AKLSGPNGVDY (SEQ ID NO: 197).

In some embodiments, LC-CDR1 is SSDVGGYNF (SEQ ID NO:294), SSDVGGYEY (SEQ ID NO:159), SRDVGGYNY (SEQ ID NO:150), NSDVGGYNY (SEQ ID NO:300), SSDVGGYDY (SEQ ID NO:128), SSDVGGYNY (SEQ ID NO:107), ISDVGGYNY (SEQ ID NO:122), SSDVGDYDY (SEQ ID NO:317), SSDVAGYNY (SEQ ID NO:330), SSDVGTYNY (SEQ ID NO:344), NTDVGAYNY (SEQ ID NO:272), SNDIGAYNY (SEQ ID NO:306), SSDVGAYNY (SEQ ID NO:110), SSDIGVYNY (SEQ ID NO:347), SSDIGGYNY (SEQ ID NO:326), SSDVGAYDY (SEQ ID NO:333), GSDVGAYDY (SEQ ID NO:322), SGDVGTYNY (SEQ ID NO:298), SGDVGTYDY (SEQ ID NO:302), INSQAY (SEQ ID NO:352), QIISSY (SEQ ID NO:155), QSSSY (SEQ ID NO:356), VSSSY (SEQ ID NO:367), SEQ ID NO:107), RSDIGGYDY (SEQ ID NO:290), RRDVGGYDF (SEQ ID NO:339), SSNVGGYNY (SEQ ID NO:284), GSNVGGYNY (SEQ ID NO:349) or QSVNSAY (SEQ ID NO: 359).

In some embodiments, LC-CDR2 is one of DVS (SEQ ID NO:108), DVV (SEQ ID NO:275), DVT (SEQ ID NO:123), DVD (SEQ ID NO:295), DVN (SEQ ID NO:291), DVG (SEQ ID NO:133), AAS (SEQ ID NO:102), or GAS (SEQ ID NO: 138).

In a preferred embodiment, LC-CDR3 is CSYAGSYTWV (SEQ ID NO:131), SSYAGSYTWV (SEQ ID NO:124), CSYAGSYSWV (SEQ ID NO:273), CSYAGGYTWV (SEQ ID NO:276), NSYAGSYTWV (SEQ ID NO:278), CSYAGSYVWV (SEQ ID NO:285), CSYAGRYTWI (SEQ ID NO:296), CSYAGRYTWM (SEQ ID NO:336), CSYAGTYTWV (SEQ ID NO:340), CSYAGFYTWV (SEQ ID NO:345), CSYAGSHIWV (SEQ ID NO:308), CSYAGRYTWV (SEQ ID NO:313), CSYAGNYTWM (SEQ ID NO:315), CSYAGSYTWI (SEQ ID NO: 63324), ASYAGNYNWV (SEQ ID NO:304), SSYAGGYTWV (SEQ ID NO:364), SSYTNSRTWV (SEQ ID NO:292), SSYTSNTTWV (SEQ ID NO:311), SSYTSSTTWV (SEQ ID NO:320), SSYTSSSSWV (SEQ ID NO:109), SSYTSSISWV (SEQ ID NO:288), SSYTSSITWV (SEQ ID NO:130), QQSYSTPSWT (SEQ ID NO:354), 36360 (SEQ ID NO: 36360), QQSYSTPTWT (SEQ ID NO:156), SSFTTSIAWV (SEQ ID NO:268), SSFTSSTTWV (SEQ ID NO:281), SSFATSISWV (SEQ ID NO:408), NSYTSGSTWV (SEQ ID NO:362), ASYTRSSVWV (SEQ ID NO:334), QQSSTSPTWA (SEQ ID NO:357) or SSYRSGSTLGVRRRDQADRPR (SEQ ID NO: 282).

HC-CDR1:GFTFSSYG(SEQ ID NO:186)

HC-CDR2:ISYDGSNK(SEQ ID NO:184)

HC-CDR3:AKIGATDPLDY(SEQ ID NO:187)；

or

HC-CDR1:GFTFSSYA(SEQ ID NO:190)

HC-CDR2:ISYDGSNK(SEQ ID NO:184)

HC-CDR3:ARIMGYDYGDYDVVDY(SEQ ID NO:199)；

Or

HC-CDR1:GFTFGSYG(SEQ ID NO:234)

HC-CDR2:ISYDGSNK(SEQ ID NO:184)

HC-CDR3:AKIGATDPLDY(SEQ ID NO:187)；

Or

HC-CDR1:GFTFSSYG(SEQ ID NO:186)

HC-CDR2:ISYDGSNR(SEQ ID NO:381)

HC-CDR3:AKIGATDPLDY(SEQ ID NO:187)；

Or

HC-CDR1:GFTFSSYG(SEQ ID NO:186)

HC-CDR2:ISYDGSNK(SEQ ID NO:184)

HC-CDR3:ARIMGYDYGDYDVVDY(SEQ ID NO:199)；

Or

HC-CDR1:GFTFSSYG(SEQ ID NO:186)

HC-CDR2:ISYDGSNK(SEQ ID NO:184)

HC-CDR3:AKGGKSYYGFDY(SEQ ID NO:207)；

Or

HC-CDR1:GFTFGSYG(SEQ ID NO:234)

HC-CDR2:ISYDGSNK(SEQ ID NO:184)

HC-CDR3:AKGSYYFDY(SEQ ID NO:235)；

Or

HC-CDR1:GFTFSSYG(SEQ ID NO:186)

HC-CDR2:ISYDGSNK(SEQ ID NO:184)

HC-CDR3:AKLSGPNGVDY(SEQ ID NO:197).

LC-CDR1:SSDVGAYNY(SEQ ID NO:110)

LC-CDR2:DVS(SEQ ID NO:108)

LC-CDR3:SSFTTSIAWV(SEQ ID NO:268)；

or

LC-CDR1:SSDVGGYNY(SEQ ID NO:107)

LC-CDR2:DVS(SEQ ID NO:108)

LC-CDR3:CSYAGSYTWV(SEQ ID NO:131)；

Or

LC-CDR1:SSDVGGYNY(SEQ ID NO:107)

LC-CDR2:DVS(SEQ ID NO:108)

LC-CDR3:SSYAGSYTWV(SEQ ID NO:124)；

Or

LC-CDR1:NTDVGAYNY(SEQ ID NO:272)

LC-CDR2:DVS(SEQ ID NO:108)

LC-CDR3:CSYAGSYSWV(SEQ ID NO:273)；

Or

LC-CDR1:SSDVGGYNY(SEQ ID NO:107)

LC-CDR2:DVV(SEQ ID NO:275)

LC-CDR3:CSYAGGYTWV(SEQ ID NO:276)；

Or

LC-CDR1:SSDVGGYNY(SEQ ID NO:107)

LC-CDR2:DVS(SEQ ID NO:108)

LC-CDR3:NSYAGSYTWV(SEQ ID NO:278)；

Or

LC-CDR1:SRDVGGYNY(SEQ ID NO:150)

LC-CDR2:DVS(SEQ ID NO:108)

LC-CDR3:CSYAGSYTWV(SEQ ID NO:131)；

Or

LC-CDR1:SSDVGGYNY(SEQ ID NO:107)

LC-CDR2:DVS(SEQ ID NO:108)

LC-CDR3:SSFTSSTTWV(SEQ ID NO:281)；

Or

LC-CDR1:SSDVGGYNY(SEQ ID NO:107)

LC-CDR2:DVS(SEQ ID NO:108)

LC-CDR3:SSYRSGSTLGVRRRDQADRPR(SEQ ID NO:282)；

Or

LC-CDR1:SSNVGGYNY(SEQ ID NO:284)

LC-CDR2:DVS(SEQ ID NO:108)

LC-CDR3:CSYAGSYVWV(SEQ ID NO:285)；

Or

LC-CDR1:SSDVGGYNY(SEQ ID NO:107)

LC-CDR2:DVT(SEQ ID NO:123)

LC-CDR3:CSYAGGYTWV(SEQ ID NO:276)；

Or

LC-CDR1:SSDVGGYNY(SEQ ID NO:107)

LC-CDR2:DVS(SEQ ID NO:108)

LC-CDR3:SSYTSSISWV(SEQ ID NO:288)；

Or

LC-CDR1:RSDIGGYDY(SEQ ID NO:290)

LC-CDR2:DVN(SEQ ID NO:291)

LC-CDR3:SSYTSSITWV(SEQ ID NO:130)；

Or

LC-CDR1:SSDVGGYNY(SEQ ID NO:107)

LC-CDR2:DVS(SEQ ID NO:108)

LC-CDR3:SSYTNSRTWV(SEQ ID NO:292)；

Or

LC-CDR1:SSDVGGYNF(SEQ ID NO:294)

LC-CDR2:DVD(SEQ ID NO:295)

LC-CDR3:CSYAGRYTWI(SEQ ID NO:296)；

Or

LC-CDR1:SGDVGTYNY(SEQ ID NO:298)

LC-CDR2:DVS(SEQ ID NO:108)

LC-CDR3:NSYAGSYTWV(SEQ ID NO:278)；

Or

LC-CDR1:NSDVGGYNY(SEQ ID NO:300)

LC-CDR2:DVS(SEQ ID NO:108)

LC-CDR3:CSYAGSYTWV(SEQ ID NO:131)；

Or

LC-CDR1:SGDVGTYDY(SEQ ID NO:302)

LC-CDR2:DVS(SEQ ID NO:108)

LC-CDR3:NSYAGSYTWV(SEQ ID NO:278)；

Or

LC-CDR1:SSNVGGYNY(SEQ ID NO:284)

LC-CDR2:DVS(SEQ ID NO:108)

LC-CDR3:ASYAGNYNWV(SEQ ID NO:304)；

Or

LC-CDR1:SNDIGAYNY(SEQ ID NO:306)

LC-CDR2:DVN(SEQ ID NO:291)

LC-CDR3:CSYAGSYSWV(SEQ ID NO:273)；

Or

LC-CDR1:SSDVGGYNY(SEQ ID NO:107)

LC-CDR2:DVT(SEQ ID NO:123)

LC-CDR3:CSYAGSHIWV(SEQ ID NO:308)；

Or

LC-CDR1:SSDVGGYNY(SEQ ID NO:107)

LC-CDR2:DVS(SEQ ID NO:108)

LC-CDR3:CSYAGSYSWV(SEQ ID NO:273)；

Or

LC-CDR1:SSDVGGYDY(SEQ ID NO:128)

LC-CDR2:DVT(SEQ ID NO:123)

LC-CDR3:SSYTSNTTWV(SEQ ID NO:311)；

Or

LC-CDR1:SSDVGGYDY(SEQ ID NO:128)

LC-CDR2:DVT(SEQ ID NO:123)

LC-CDR3:CSYAGRYTWV(SEQ ID NO:313)；

Or

LC-CDR1:SSDVGGYNY(SEQ ID NO:107)

LC-CDR2:DVS(SEQ ID NO:108)

LC-CDR3:CSYAGNYTWM(SEQ ID NO:315)；

Or

LC-CDR1:SSDVGDYDY(SEQ ID NO:317)

LC-CDR2:DVT(SEQ ID NO:123)

LC-CDR3:CSYAGSYTWV(SEQ ID NO:131)；

Or

LC-CDR1:SSDVGGYNY(SEQ ID NO:107)

LC-CDR2:DVS(SEQ ID NO:108)

LC-CDR3:SSYTSSTTWV(SEQ ID NO:320)；

Or

LC-CDR1:GSDVGAYDY(SEQ ID NO:322)

LC-CDR2:DVN(SEQ ID NO:291)

LC-CDR3:SSFATSISWV(SEQ ID NO:408)；

Or

LC-CDR1:SSDVGGYNY(SEQ ID NO:107)

LC-CDR2:DVT(SEQ ID NO:123)

LC-CDR3:CSYAGSYTWI(SEQ ID NO:324)；

Or

LC-CDR1:SSDIGGYNY(SEQ ID NO:326)

LC-CDR2:DVS(SEQ ID NO:108)

LC-CDR3:CSYAGSYTWV(SEQ ID NO:131)；

Or

LC-CDR1:SSDVGGYNF(SEQ ID NO:294)

LC-CDR2:DVN(SEQ ID NO:291)

LC-CDR3:CSYAGGYTWV(SEQ ID NO:276)；

Or

LC-CDR1:SSDVGGYEY(SEQ ID NO:159)

LC-CDR2:DVT(SEQ ID NO:123)

LC-CDR3:CSYAGSYTWV(SEQ ID NO:131)；

Or

LC-CDR1:SSDVAGYNY(SEQ ID NO:330)

LC-CDR2:DVT(SEQ ID NO:123)

LC-CDR3:CSYAGSYTWV(SEQ ID NO:131)；

Or

LC-CDR1:SSDVGAYNY(SEQ ID NO:110)

LC-CDR2:DVN(SEQ ID NO:291)

LC-CDR3:CSYAGSYTWV(SEQ ID NO:131)；

Or

LC-CDR1:SSDVGAYDY(SEQ ID NO:333)

LC-CDR2:DVT(SEQ ID NO:123)

LC-CDR3:ASYTRSSVWV(SEQ ID NO:334)；

Or

LC-CDR1:SSDVGGYNY(SEQ ID NO:107)

LC-CDR2:DVN(SEQ ID NO:291)

LC-CDR3:CSYAGRYTWM(SEQ ID NO:336)；

Or

LC-CDR1:ISDVGGYNY(SEQ ID NO:122)

LC-CDR2:DVT(SEQ ID NO:123)

LC-CDR3:SSYAGSYTWV(SEQ ID NO:124)；

Or

LC-CDR1:RRDVGGYDF(SEQ ID NO:339)

LC-CDR2:DVS(SEQ ID NO:108)

LC-CDR3:CSYAGTYTWV(SEQ ID NO:340)；

Or

LC-CDR1:SSDVGGYNY(SEQ ID NO:107)

LC-CDR2:DVG(SEQ ID NO:133)

LC-CDR3:CSYAGGYTWV(SEQ ID NO:276)；

Or

LC-CDR1:SSDVGAYNY(SEQ ID NO:110)

LC-CDR2:DVS(SEQ ID NO:108)

LC-CDR3:CSYAGSYTWV(SEQ ID NO:131)；

Or

LC-CDR1:SSDVGTYNY(SEQ ID NO:344)

LC-CDR2:DVS(SEQ ID NO:108)

LC-CDR3:CSYAGFYTWV(SEQ ID NO:345)；

Or

LC-CDR1:SSDIGVYNY(SEQ ID NO:347)

LC-CDR2:DVS(SEQ ID NO:108)

LC-CDR3:CSYAGSYTWV(SEQ ID NO:131)；

Or

LC-CDR1:GSNVGGYNY(SEQ ID NO:349)

LC-CDR2:DVS(SEQ ID NO:108)

LC-CDR3:CSYAGTYTWV(SEQ ID NO:340)；

Or

LC-CDR1:SSDVGGYNY(SEQ ID NO:107)

LC-CDR2:DVT(SEQ ID NO:123)

LC-CDR3:SSYAGSYTWV(SEQ ID NO:124)；

Or

LC-CDR1:SSDVGGYNY(SEQ ID NO:107)

LC-CDR2:DVS(SEQ ID NO:108)

LC-CDR3:SSYTSSSSWV(SEQ ID NO:109)；

Or

LC-CDR1:QAINSY(SEQ ID NO:352)

LC-CDR2:AAS(SEQ ID NO:102)

LC-CDR3:QQSYSTPSWT(SEQ ID NO:354)；

Or

LC-CDR1:QSFSSSY(SEQ ID NO:356)

LC-CDR2:GAS(SEQ ID NO:138)

LC-CDR3:QQSSTSPTWA(SEQ ID NO:357)；

Or

LC-CDR1:QSVNSAY(SEQ ID NO:359)

LC-CDR2:GAS(SEQ ID NO:138)

LC-CDR3:QQSYSDPRWT(SEQ ID NO:360)；

Or

LC-CDR1:QIISSY(SEQ ID NO:155)

LC-CDR2:AAS(SEQ ID NO:102)

LC-CDR3:QQSYSTPTWT(SEQ ID NO:156)；

Or

LC-CDR1:SSDVGGYNY(SEQ ID NO:107)

LC-CDR2:DVN(SEQ ID NO:291

LC-CDR3:NSYTSGSTWV(SEQ ID NO:362)；

Or

LC-CDR1:ISDVGGYNY(SEQ ID NO:122)

LC-CDR2:DVT(SEQ ID NO:123)

LC-CDR3:SSYAGGYTWV(SEQ ID NO:364)；

Or

LC-CDR1:QIISSY(SEQ ID NO:155)

LC-CDR2:AAS(SEQ ID NO:102)；

Or

LC-CDR1:QSVSSSY(SEQ ID NO:367)

LC-CDR2:GAS(SEQ ID NO:138)

LC-CDR3:QQSYSTPTWT(SEQ ID NO:156)。

the light chain includes LC-CDR1, LC-CDR2, LC-CDR3, has at least 85% overall sequence identity to LC-CDR1, LC-CDR1: x₁₃₈X₁₃₉DVGGYX₁₄₀X₁₄₁(SEQ ID NO:393),SSDVX₁₄₂X₁₄₃YX₁₄₄Y(SEQ ID NO:394),X₁₄₅X₁₄₆DX₁₄₇GAYNY(SEQ ID NO:395),SSDIGX₁₄₈YNY(SEQ ID NO:396),X₁₄₉SDVGAYDY(SEQ ID NO:397),SGDVGTYX₁₅₀Y(SEQ ID NO:398),QX₁₅₁IX₁₅₂SY(SEQ ID NO:399),QSX₁₅₃SSSY(SEQ ID NO:400),RX₁₅₄DX₁₅₅GGYDX₁₅₆(SEQ ID NO:401), SSNVGGYNY (SEQ ID NO:284), GSNVGGYNY (SEQ ID NO:214) or QSVNSAY (SEQ ID NO: 359); LC-CDR 2: DVX₁₅₇(SEQ ID NO:402) or X₁₅₈One of AS (SEQ ID NO: 403); LC-CDR 3: x₁₅₉SYAGX₁₆₀X₁₆₁X₁₆₂WX₁₆₃(SEQ ID NO:404),SSYTX₁₆₄X₁₆₅X₁₆₆X₁₆₇WV(SEQ ID NO:405),QQSYSX₁₆₈PX₁₆₉WT(SEQ ID NO:406),SSFX₁₇₀X₁₇₁SX₁₇₂X₁₇₃One of WV (SEQ ID NO:407), NSYTSGSTWV (SEQ ID NO:362), ASYTRSSVWV (SEQ ID NO:334), QQSSTSPTWA (SEQ ID NO:357), or SSYRSGSTLGVRRRDQADRPR (SEQ ID NO: 282); and

the heavy chain includes HC-CDR1, HC-CDR2, HC-CDR3, has at least 85% overall sequence identity with HC-CDR1, HC-CDR 1: GFTFX₁₇₄SYX₁₇₅(SEQ ID NO:409)；HC-CDR2：ISYDGSNX₁₇₆(SEQ ID NO: 410); HC-CDR3: AKIGATDPLDY (SEQ ID NO:187), ARIMGYDYGDYDVVDY (SEQ ID NO:199), AKLSGPNGVDY (SEQ ID NO:197) or AKGX₁₇₇X₁₇₈SYYX₁₇₉FDY(SEQ ID NO:411)；

the light chain sequence is similar to that of SEQ ID NOs: 267. 269, 270, 271, 274, 277, 279, 280, 540, 283, 286, 287, 289, 353, 293, 297, 299, 301, 303, 305, 307, 309, 310, 312, 314, 316, 318, 319, 321, 323, 325, 327, 328, 329, 331, 332, 335, 337, 338, 341, 342, 343, 346, 348, 214, 350, 13, 3, 351, 355, 358, 35, 361, 363, 365, 366, or 20 has at least 85% sequence identity to the light chain sequence; and

the heavy chain sequence is similar to SEQ ID NO: 53. the heavy chain sequence of one of 368, 369, 370, 371, 372, 373, 374, 375, 376, 377, 378, 379, 380, 382, 383, 384, 385, 386, 387, 388, 389, 85, 390, 73, 391 or 392 has at least 85% sequence identity.

In another aspect, the invention provides an optionally isolated antibody or antigen-binding fragment capable of binding IL-11 comprising an amino acid sequence having at least 85% sequence identity to the sequence of one of SEQ ID NOs:412 to 475.

In another aspect, the invention provides an optionally isolated antibody or antigen-binding fragment capable of binding to IL-11, comprising amino acid sequences i) to vi):

i) LC-CDR1: ENVVTY (SEQ ID NO:555), QSIGTS (SEQ ID NO:558), QSLLYNSSQKNY (SEQ ID NO:562) or QDVGTA (SEQ ID NO: 565);

ii)LC-CDR2:X₁₈₄AS(SEQ ID NO:569)；

iii)LC-CDR3:X₁₈₅QX₁₈₆X₁₈₇SX₁₈₈X₁₈₉X₁₉₀T(SEQ ID NO:570)；

iv)HC-CDR1:GYTFTX₁₈₀YX₁₈₁(SEQ ID NO:567)；

v)HC-CDR2:INPX₁₈₂NGGX₁₈₃(SEQ ID NO:568) or IYPRSSNT (SEQ ID NO: 552);

vi) HC-CDR3: ARGELGHWYFDV (SEQ ID NO:544), AREGPYGYTWFAY (SEQ ID NO:547), ARNPSLYDGYLDC (SEQ ID NO:550) or ARANWVGYFDV (SEQ ID NO: 553);

or a variant thereof, wherein one or more of the amino acids of one or more of sequences i) to vi) is substituted with another amino acid;

wherein X₁₈₀Either D or S, X₁₈₁N or G, X₁₈₂H, D or N, X₁₈₃P, T or I, X₁₈₄G, Y or W, X₁₈₅Q or G

X₁₈₆Y, G or S, X₁₈₇Y, N or S, X₁₈₈Y or W, X₁₈₉P or absent, and X₁₉₀L, Y or R.

In some embodiments, HC-CDR1 is one of GYTFTDYN (SEQ ID NO:542) or GYTFTSYG (SEQ ID NO: 228).

In some embodiments, HC-CDR2 is one of INPHNGGP (SEQ ID NO: 543), INPDNGGT (SEQ ID NO: 546), INPNNGGI (SEQ ID NO: 549), or IYPRSSNT (SEQ ID NO: 552).

In some embodiments, HC-CDR3 is one of ARGELGHWYFDV (SEQ ID NO:544), AREGPYGYTWFAY (SEQ ID NO:547), ARNPSLYDGYLDC (SEQ ID NO:550) or ARANWVGYFDV (SEQ ID NO: 553).

In some embodiments, LC-CDR1 is one of ENVVTY (SEQ ID NO:555), QSIGTS (SEQ ID NO:558), QSLLYNSSQKNY (SEQ ID NO:562) or QDVGTA (SEQ ID NO: 565).

In some embodiments, the LC-CDR2 is one of GAS (SEQ ID NO:138), YAS (SEQ ID NO: 559) or WAS (SEQ ID NO: 563).

In some embodiments, LC-CDR3 is one of GQGYSYPYT (SEQ ID NO: 556), QQSNSWPLT (SEQ ID NO: 560), QQYYSYPLT (SEQ ID NO: 563), or QQYSSYRT (SEQ ID NO: 566).

HC-CDR1:GYTFTDYN(SEQ ID NO:542)

HC-CDR2:INPHNGGP(SEQ ID NO:543)

HC-CDR3:ARGELGHWYFDV(SEQ ID NO:544)；

or

HC-CDR1:GYTFTDYN(SEQ ID NO:542)

HC-CDR2:INPDNGGT(SEQ ID NO:546)

HC-CDR3:AREGPYGYTWFAY(SEQ ID NO:547)；

Or

HC-CDR1:GYTFTDYN(SEQ ID NO:542)

HC-CDR2:INPNNGGI(SEQ ID NO:549)

HC-CDR3:ARNPSLYDGYLDC(SEQ ID NO:550)；

Or

HC-CDR1:GYTFTSYG(SEQ ID NO:228)

HC-CDR2:IYPRSSNT(SEQ ID NO:552)

HC-CDR3:ARANWVGYFDV(SEQ ID NO:553)。

LC-CDR1:ENVVTY(SEQ ID NO:555)

LC-CDR2:GAS(SEQ ID NO:138)

LC-CDR3:GQGYSYPYT(SEQ ID NO:556)；

or

LC-CDR1:QSIGTS(SEQ ID NO:558)

LC-CDR2:YAS(SEQ ID NO:559)

LC-CDR3:QQSNSWPLT(SEQ ID NO:560)；

Or

LC-CDR1:QSLLYNSSQKNY(SEQ ID NO:562)

LC-CDR2:WAS(SEQ ID NO:563)

LC-CDR3:QQYYSYPLT(SEQ ID NO:581)；

Or

LC-CDR1:QDVGTA(SEQ ID NO:565)

LC-CDR2:WAS(SEQ ID NO:563)

LC-CDR3:QQYSSYRT(SEQ ID NO:566)。

the light chain includes LC-CDR1, LC-CDR2, LC-CDR3, has at least 85% overall sequence identity to LC-CDR1, LC-CDR1: ENVVTY (SEQ ID NO:555), QSIGTS (SEQ ID NO:558), QSLLYNSSQKNY (SEQ ID NO:562) or QDVGTA (SEQ ID NO: 565); LC-CDR 2: x₁₈₄AS(SEQ ID NO:569)；LC-CDR3:X₁₈₅QX₁₈₆X₁₈₇SX₁₈₈X₁₈₉X₁₉₀T (SEQ ID NO: 570); and

the heavy chain includes HC-CDR1, HC-CDR2, HC-CDR3, has at least 85% overall sequence identity with HC-CDR1, HC-CDR 1: GYTFTX₁₈₀YX₁₈₁(SEQ ID NO:567)；HC-CDR2：INPX₁₈₂NGGX₁₈₃(SEQ ID NO:568) or IYPRSSNT (SEQ ID NO: 552); HC-CDR3: ARGELGHWYFDV (SEQ ID NO:544), AREGPYGYTWFAY (SEQ ID NO:547), ARNPSLYDGYLDC (SEQ ID NO:550) or ARANWVGYFDV (SEQ ID NO: 553);

the light chain sequence is similar to that of SEQ ID NOs: 554. 557, 561, or 564 has at least 85% sequence identity to the light chain sequence; and

heavy chain sequences and SEQ ID NOs: 541. the heavy chain sequence of one of 545,548 or 551 has at least 85% sequence identity.

Detailed description of the invention

The present invention relates to antibodies specific for interleukin-11 (IL-11). The present invention describes the identification of IL-11/IL-11R signaling as a key mediator of fibrosis, as well as the production and functional characterization of anti-IL-11 antibodies. Therapeutic and diagnostic uses of the antibodies are also described.

IL-11 and IL-11 mediated signaling

The antibodies and fragments of the invention bind to interleukin 11. Interleukin 11(IL-11), also known as adipogenesis inhibitory factor, is a pleiotropic cytokine, a member of the pleiotropic cytokine and IL-6 cytokine family, including IL-6, IL-11, IL-27, IL-31, oncostatin M (OSM), Leukemia Inhibitory Factor (LIF), cardiotrophin-1 (CT-1), cardiotrophin-like cytokine (CLC), ciliary neurotrophic factor (CNTF) and neurotrophin (NP-1).

IL-11 is transcribed with a classical signal peptide, ensuring efficient secretion by the cell. The immature form of human IL-11 is a 199 amino acid polypeptide, while the mature form of IL-11 encodes a 178 amino acid residue protein (Garbers and Scheller, biol. chem.2013; 394 (9): 1145-. The human IL-11 amino acid sequence is available under UniProt accession number P20809 (P20809.1GI: 124294). Recombinant human IL-11 (Omepleren interleukin) is also commercially available. IL-11 from other species, including mice, rats, pigs, cows, several bony fishes and primates, has also been cloned and sequenced.

In this specification, "IL-11" refers to IL-11 from any species, including isoforms, fragments, variants or homologs of IL-11 from any species.

In some embodiments, IL-11 is a mammalian IL-11 (e.g., cynomolgus monkey, human, and/or rodent (e.g., rat and/or mouse) IL-11). Isoforms, fragments, variants or homologs of IL-11 may optionally be characterized as having at least 70%, preferably 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99% or 100% amino acid sequence identity to the amino acid sequence of an immature or mature IL-11 from a given species (e.g., human). Isoforms, fragments, variants or homologs of IL-11 can optionally be characterized by the ability to bind IL-11Ra (preferably from the same species) and stimulate signal transduction in cells expressing IL-11Ra and gp130 (e.g., as described by Curtis et al, blood, 1997, 90 (11); or Karpovich et al, mol.hum.reprod.20039 (2): 75-80). Fragments of IL-11 can have any length (number of amino acids), but can optionally be at least 25% of the length of mature IL-11, and can have a maximum length of one of 50%, 75%, 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% of the length of mature IL-11. Fragments of IL-11 may have a minimum length of 10 amino acids and a maximum length of one of 15, 20, 25, 30, 40, 50, 100, 110, 120, 130, 140, 150, 160, 170,180, 190, or 195 amino acids.

IL-11 signals through the homodimer of ubiquitously expressed beta-receptor glycoprotein 130(gp 130; also known as glycoprotein 130, IL-6ST, IL-6-beta or CD 130). Gp130 is a transmembrane protein that forms a subunit of the type I cytokine receptor with the IL-6 receptor family. Specificity is obtained by the IL-11 alpha receptor alone (IL-11 Ra), which is not directly involved in signal transduction, although the initial cytokine binding event to the alpha receptor results in the formation of a final complex with the beta receptor. IL-11 activates downstream signaling pathways, primarily the mitogen-activated protein kinase (MAPK) -cascade and the Janus kinase/Signal transducer and activator of transcription (Jak/STAT) pathways (Garbers and Scheller, supra).

Human IL-11Ra is a 422 amino acid polypeptide (Genbank accession NP-001136256.1 GI: 218505839) and shares-85% nucleotide and amino acid sequence identity with mouse IL-11Ra (Du and Williams, Vol. 89, Vol. 11, 1997, 6/1). Two isoforms of IL-11R α have been reported that differ in the cytoplasmic domain (Du and Williams, supra). In some embodiments as used herein, IL-11Ra can be IL-11Ra isoform 1 or IL-11Ra isoform 2.

The IL-11 receptor alpha chain (IL-11R alpha) shares many structural and functional similarities with the IL-6 receptor alpha chain (IL-6R alpha). The extracellular domain shows 24% amino acid identity, including the characteristically conserved Trp-Ser-X-Trp-Ser (wsxws) motif. The short cytoplasmic domain (34 amino acids) lacks the regions of blocks 1 and 2 required for activation of the JAK/STAT signaling pathway.

IL-11R α binds its ligand with low affinity (Kd 10nmol/L) and alone is insufficient to transduce biological signals. Production of high affinity receptors capable of signal transduction (Kd-400 to 800pmol/L) requires co-expression of IL-11R α and gp130 (Curtis et al (blood 1997Dec 1; 90 (11): 4403-12; Hilton et al, EMBO J13: 4765, 1994; Nandurkar et al, oncogene 12: 585, 1996). binding of IL-11 to cell surface IL-11R α induces heterodimerization, tyrosine phosphorylation, activation of gp130 and MAPK, and/or Jak/STAT signaling as described above.

The receptor binding site on mouse IL-11 has been mapped and three sites, sites I, II and III, have been identified. The binding to gp130 is reduced by substitution of the domain at site II and substitution of the domain at site III. The site III mutant showed no detectable agonist activity and had IL-11Ra antagonist activity (cytokine inhibitor Chapter 8; edited by Gennaro Ciliberto and Rocco Savino, Marcel Dekker, Inc.2001).

In principle, soluble IL-11R α can also form a biologically active soluble complex with IL-11 (Pflanz et al, 1999FEBS Lett, 450, 117-: similar to IL-6, IL-11, in some cases soluble IL-11R α can be bound before binding to cell surface gp130 (Garbers and Scheller, supra). Curtis et al (blood 1997Dec 1; 90 (11): 4403-12) described the expression of soluble mouse IL-11 receptor alpha chain (sIL-11R alpha) and examined signaling in gp130 expressing cells. In the presence of gp130 but in the absence of transmembrane IL-11R, sIL-11R mediates IL-11 dependent differentiation of M1 leukemia cells and proliferation of Ba/F3 cells as well as early intracellular events, including phosphorylation of gp130, STAT3, and SHP2, similar to signaling through transmembrane IL-11R.

Activation of signaling through cell membrane-bound gp130 by IL-11 bound to soluble IL-11R α has been recently demonstrated (Lokau et al, 2016 cell report 14, 1761-1773). This so-called IL-11 trans-signaling may be a very important component of IL-11-mediated signaling, and may even be the most common form of IL-11-mediated signaling, because although IL-11R α expression is limited to a relatively small fraction of cell types, gp130 is expressed on a variety of cell types.

As used herein, "IL-11 trans-signaling" is used to refer to signaling triggered by the binding of IL-11 to gp130 that binds IL-11 Ra. IL-11 may bind to IL-11Ra as a non-covalent complex. gp130 is membrane-bound and expressed by a cell, wherein the expression of gp130 is measured in IL-11: signaling occurs upon binding of the IL-11ra complex to gp 130. In some embodiments, IL-11R α can be soluble IL-11R α. In some embodiments, the soluble IL-11Ra is a soluble (secreted) isoform of IL-11Ra (e.g., lacks a transmembrane domain). In some embodiments, soluble IL-11Ra is a release product of proteolytic cleavage of the extracellular domain of a cell membrane-bound IL-11 Ra. In some embodiments, IL-11R α can be cell membrane bound, and gp130 signaling can be triggered by binding to IL-11, the IL-11 and cell membrane bound IL-11R α binding.

In the present specification, IL-11 receptor (IL-11R) refers to a polypeptide capable of binding IL-11 and inducing signal transduction in gp 130-expressing cells. The IL-11 receptor may be from any species, and includes isoforms, fragments, variants or homologs of the IL-11 receptor from any species. In a preferred embodiment, the species is human (homo sapiens). In some embodiments, the IL-11 receptor may be IL-11R α. Isoforms, fragments, variants or homologs of IL-11Ra may optionally be characterized as having at least 70%, preferably 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99% or 100% amino acid sequence identity to the amino acid sequence of IL-11Ra of a given species (e.g., human). Isoforms, fragments, variants or homologs of IL-11Ra may optionally be characterized by an ability to bind IL-11 (preferably from the same species) and stimulate signal transduction in cells expressing IL-11Ra and gp130 (e.g., as described by Curtis et al, blood, 1997, 90(11) or Karpovich et al, mol.hum.Reprod.20039 (2): 75-80). Fragments of the IL-11 receptor can have any length (number of amino acids), but can optionally be at least 25% of the length of mature IL-11Ra and have a maximum length that is one of 50%, 75%, 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% of the length of mature IL-11 Ra. Fragments of the IL-11 receptor fragment may have a minimum length of 10 amino acids and a maximum length of one of 15, 20, 25, 30, 40, 50, 100, 110, 120, 130, 140, 150, 160, 170,180, 190, 200, 250, 300, 400, or 415 amino acids.

TGF β 1 has been shown to induce IL-11 expression in fibroblasts (Elias et al, 1994J. Immunol.152, 2421-2429).

IL-11 has been proposed to act primarily as a platelet growth factor, which supports the use of recombinant IL-11(neumega (opreclekin)) as a therapeutic agent to increase platelet count.

The role of IL-11 in fibrosis is not clear. Most studies indicate anti-fibrotic function of IL-11 in the heart (Obana et al, 2010 cycle 121, 684-. Kurahara et al, j.smoothen Muscle res.2016; 52: 78-92 describes IL-11 as an anti-fibrotic cytokine and suggests that IL-11 inhibits alpha SMA expression.

IL-11 is also known as an anti-inflammatory factor in several tissues and chronic inflammatory diseases (Trepicchia and Dorner, 1998 expert opinion investigating drugs 7, 1501-1504; Zhu et al, 2015 public science library journal 10, e 0126296). These studies indicate that the observed secretion of IL-11 in response to TGF-beta 1 is a protective mechanism.

On the other hand, it has been suggested that IL-11 signaling may be involved in the pathology of pulmonary diseases. Inhibition of IL-11 by antibodies or mutated recombinant IL-11 in tuberculosis models revealed a positive feedback loop in vivo and reduced lung histopathology (Kapina et al, 2011J. am. Sci. J. 6, e 21878; Shepelkova et al, 2016J. infectious disease 214, jiw176), fibrosis of mouse airways has been associated with IL-11 expression (Tang et al, 1996J. Clin. Res. 98, 2845-2853). IL-11 signaling is associated with this mechanism when the profibrotic function of IL-13 in lung tissue is studied in IL-11 RA-/-mice (Chen et al, 2005J. Immunol.174, 2305-2313).

IL-11 was also found to be elevated in the airways of patients with severe asthma (Minshall et al, 2000 breathing study 14, 1-14), over-expressed in the lungs of patients with IPF (Lindahl et al, 2013 breathing study 14, 1-14) and elevated in skin lesions of patients with atopic dermatitis (Toda et al, 2003J Allergy Clin Immun 111, 875-. It is uncertain whether these associations are due to increased IL-11 gene/protein expression as a response to a disease process, or whether IL-11 is an effector of a disease process.

Antibodies and antigen binding fragments

The antibodies and antigen-binding fragments of the invention bind to IL-11 (Interleukin 11). In some embodiments, the antibody/fragment binds to human IL-11. In some embodiments, the antibody/fragment binds to non-human primate IL-11. In some embodiments, the antibody/fragment binds mouse IL-11.

"antibody" includes fragments and derivatives thereof, or synthetic antibodies or fragments of synthetic antibodies. As used herein, an antibody is a polypeptide that is capable of specifically binding to a target molecule of interest (i.e., an antigen specific for the antibody). The antibodies of the invention may be provided in isolated form.

Given the modern technology associated with monoclonal antibody technology, antibodies can be made against most antigens. The antigen-binding portion can be a portion of an antibody (e.g., a Fab fragment) or a synthetic antibody fragment (e.g., a single chain Fv fragment [ ScFv ]). Monoclonal antibodies appropriate for the selected antigen can be prepared by known techniques, for example as described in "monoclonal antibodies: technical manual ", H Zola (CRC press, 1988) and" monoclonal hybridoma antibodies: techniques and applications ", those disclosed in JGR Hurrell (CRC press, 1982). Neuberger et al (1988, second part of the 8 th International society for biotechnology 792-799) discusses chimeric antibodies.

Monoclonal antibodies (mabs) may be used in the methods of the invention and are a homogeneous population of antibodies that specifically target a single epitope on an antigen.

Antigen binding fragments of antibodies, such as Fab and Fab, may also be used/provided₂Fragments, as they may be genetically engineered antibodies and antibody fragments. Variable heavy chain (V) of antibody_H) And variable light chain (V)_L) The domain is involved in antigen recognition, a fact first recognized in early protease digestion experiments. Further confirmation was found by "humanization" of rodent antibodies. Variable domains of rodent origin can be fused to constant domains of human origin such that the resulting antibody retains the antigen specificity of the rodent parent antibody (Morrison et al (1984) Proc. Natl. Acad. Sci. U.S. 81, 6851-6855).

In some embodiments, the antibody/fragment is a fully human antibody/fragment. Fully human antibodies/fragments are encoded by human nucleic acid sequences. Fully human antibodies/fragments lack non-human amino acid sequences.

The two most common techniques for generating fully human antibodies are: (i) phage display, in which human antibody genes are expressed in phage display libraries, and (ii) antibody production in transgenic mice engineered to have human antibody genes (described in protein chemistry development of Park and Smolen (2001) 56: 369-421). Briefly, in human antibody gene-phage display technology, genes encoding VH and VL chains are amplified by PCR and cloned from "native" human lymphocytes and assembled into libraries from which they can be expressed as disulfide-linked Fab fragments or as single chain fv (scfv) fragments. The gene encoding the Fab-or scFv-is fused to the surface coat protein of the filamentous phage and the Fab or scFv capable of binding to the target of interest can then be identified by screening the library with the antigen. Molecular evolution or affinity maturation procedures can be used to enhance the affinity of Fab/scFv fragments. In transgenic mouse technology, mice in which the endogenous murine Ig locus has been replaced by homologous recombination with its human homolog are immunized with an antigen and monoclonal antibodies are prepared by conventional hybridoma techniques to produce fully human monoclonal antibodies.

In some embodiments, the antibodies/fragments of the invention are mouse antibodies/fragments. Antibodies/fragments can be prepared by phage display using a human natural antibody gene library.

In some embodiments, the antibody/fragment is a mouse/human chimeric antibody/fragment (e.g., an antibody/antigen binding fragment comprising a mouse variable region and a human constant region). In some embodiments, the antibody/fragment is a humanized antibody/fragment (e.g., an antibody/antigen-binding fragment comprising mouse CDRs and a human framework and constant regions).

The mouse/human chimeric antibody/antigen-binding fragment can be prepared from a mouse monoclonal antibody by a chimeric process, e.g., as a human monoclonal antibody: methods and protocols, michelstanitz (editors), methods of molecular biology 1060, the schpringer protocol, Humana press (2014), described in chapter 8 thereof, in particular chapter 8, section 3.

Humanized antibodies/antigen-binding fragments can be prepared from mouse antibodies by a chimeric process, e.g., as in human monoclonal antibodies: methods and protocols, michelstanitz (editors), methods of molecular biology 1060, the schpringer protocol, Humana press (2014), chapter 7 thereof, in particular chapter 7, section 3.1, "antibody humanization".

The antigen specificity is conferred by the variable region and is absent from the constant regionIt is known from experiments involving bacterial expression of antibody fragments that each contain one or more variable regions. These molecules include Fab-like molecules (Better et al (1988) science 240, 1041); fv molecules (Skerra et al (1988) science 240, 1038); single chain fv (scFv) molecules, wherein V_HAnd V_LThe partner domains are linked by a flexible oligopeptide (Bird et al (1988) science 242, 423; Huston et al (1988) Proc. Natl. Acad. Sd. USA 85, 5879) and a single domain antibody (dAb) comprising an isolated V domain (Ward et al (1989) Nature 341, 544). An overview of the techniques involved in the synthesis of antibody fragments that retain their specific binding sites can be found in Winter and Milstein (1991) Nature 349, 293-299.

"ScFv molecule" refers to the molecule wherein V_HAnd V_LThe partner domains are covalently linked, for example, molecules linked by flexible oligopeptides.

Fab, Fv, ScFv and dAb antibody fragments can all be expressed and secreted in E.coli, and large amounts of the fragments can therefore be readily produced.

Total antibody and F (ab')₂Fragments are "bivalent". "bivalent" refers to the antibody and F (ab')₂Fragments have two antigen binding sites. In contrast, Fab, Fv, ScFv and dAb fragments are monovalent, having only one antigen binding site.

The invention provides antibodies or antigen-binding fragments that are capable of binding to IL-11. In some embodiments, an antibody or antigen-binding fragment can be isolated.

The antigen binding fragment of the present invention may be any fragment of a polypeptide capable of binding an antigen.

In some embodiments, the antigen-binding fragment comprises at least three light chain CDRs (i.e., LC-CDR1, LC-CDR2, and LC-CDR 3; also referred to herein as LC-CDR 1-3) and three heavy chain CDRs (i.e., HC-CDR1, HC-CDR2, and HC-CDR 3; also referred to herein as HC-CDR 1-3), which together define the antigen-binding region of the antibody or antigen-binding fragment. In some embodiments, the antigen-binding fragment may comprise the light chain variable region and the heavy chain variable region of the antibody or antigen-binding fragment. In some embodiments, the antigen-binding fragment may comprise a light chain polypeptide and a heavy chain polypeptide of the antibody or antigen-binding fragment.

The invention also provides a Chimeric Antigen Receptor (CAR) capable of binding IL-11 comprising one or more of the antigen-binding fragments or polypeptides of the invention. Chimeric Antigen Receptors (CARs) are recombinant receptors that provide antigen binding and T cell activation functions. CAR structures and engineering are reviewed, for example, in Dotti et al, Immunol Rev (2014)257(1), which is incorporated herein by reference in its entirety. Provided herein are antigen binding fragments of the invention as antigen binding domains of Chimeric Antigen Receptors (CARs). In some embodiments, according to any embodiment of the antibody, antigen-binding fragment, or polypeptide described herein, the CAR comprises a VL domain and a VH domain. CARs can be combined with co-stimulatory ligands, chimeric co-stimulatory receptors, or cytokines to further enhance T cell potency, specificity, and safety (Sadelain et al, rationale for Chimeric Antigen Receptor (CAR) design. Cancer discov.2013, 4 months; 3 (4): 388-398. doi: 10.1158/2159-8290.CD-12-0548, expressly incorporated herein by reference). Also provided are cells comprising a CAR of the invention. The CARs of the invention can be used to generate T cells. Engineering the CAR into T cells can be performed in vitro during culture, for transduction and expansion, e.g., occurring during T cell expansion for adoptive T cell therapy.

The invention also provides bispecific antibodies and bispecific antigen-binding fragments comprising an antibody or antigen-binding fragment of the invention. A bispecific antibody or bispecific antigen-binding fragment can comprise (i) an antibody or antigen-binding fragment of the invention, and (ii) an antibody or antigen-binding fragment specific for a target other than IL-11.

Bispecific antibodies/fragments may be provided in any suitable form, e.g., Kontermann Mabs 2012, 4 (2): 182-197, which are incorporated herein by reference in their entirety. For example, the bispecific antibody or bispecific antigen-binding fragment can be a bispecific antibody conjugate (e.g., IgG2, F (ab')₂Or CovX-body), bispecific IgG or IgG-like molecules (e.g., IgG, scFv)₄-Ig，IgG-scFv，scFv-IgG，DVD-Ig，IgG-sVD，sVD-IgG, 2 in 1-IgG, mAb²Or tandem antibodies with LC (tandmab common LC)), asymmetric bispecific IgG or IgG-like molecules (e.g.kih IgG, kih IgG with LC, CrossMab, kih IgG-scFab, mAb-Fv, charge pair or SEED bodies), a small bispecific antibody molecule (e.g.diabody (Db), dsDb, DART, scDb, tandAbs, tandem scFv (taFv), tandem dAb/VHH, triabody (triplet body), triahead, Fab-scFv or F (ab')₂-scFv₂) Bispecific Fc and C_H3 fusion proteins (e.g., taFv-Fc, diabody, scDb-C_H3, scFv-Fc-scFv, HCAb-VHH, scFv-kih-Fc or scFv-kih-C_H3) Or bispecific fusion proteins (e.g. scFv)₂Albumin, scDb-albumin, taFv-toxin, DNL-Fab₃，DNL-Fab₄-IgG，DNL-Fab₄-IgG-cytokines₂). See, specifically, Kontermann MAbs 2012, 4 (2): 182-19, fig. 2.

Methods of generating bispecific antibodies include chemical crosslinking of the antibody or antibody fragment, for example with a reducible disulfide or non-reducible thioether bond, such as described in Segal and Bast, 2001. production of bispecific antibodies. current protocol of immunology.14: IV:2.13: 2.13.1-2.13.16, the entire contents of which are incorporated herein by reference. For example, N-succinimidyl-3- (-2-pyridyldithio) -propionate (SPDP) can be used for chemical crosslinking, e.g., via Fab fragments of hinge region SH-groups, to produce disulfide-linked bispecific F (ab)₂A heterodimer. Other methods include fusion of antibody-producing hybridomas, e.g., preparation of tetraploid cells capable of secreting bispecific antibodies with polyethylene glycol, e.g., d.m. and Bast, b.j.2001. production of bispecific antibodies. IV:2.13: 2.13.1-2.13.16. Bispecific antibodies and bispecific antigen-binding fragments can also be produced recombinantly by expression of polypeptides from, for example, nucleic acid constructs encoding antigen-binding molecule polypeptides, such as antibody engineering: methods and protocols, second edition (Humana press, 2012), chapter 40: production of bispecific antibodies: dimeric and tandem scFv (Hornig and)Schwarz), or french, how to make bispecific antibodies, methods molecular medicine 2000; 40: 333, 339, the contents of both of which are hereby incorporated by reference in their entirety.

Antibodies can be produced by an affinity maturation process, wherein a modified antibody is produced that has an improved affinity of the antibody for the antigen compared to the unmodified parent antibody. Affinity matured antibodies can be generated by methods known in the art, such as Marks et al, Rio/technique 10: 779 783 (1992); barbas et al, Proc nat. acad. sci. us 91: 3809-3813 (1994); schier et al, gene 169: 147-; yelton et al, j.immunol.155: 1994-2004 (1995); jackson et al, j.immunol.154 (7): 3310-159 (1995); and Hawkins et al, j.mol.biol.226: 889-896(1992).

The invention provides antibodies described herein that further undergo a process of chain replacement, e.g., light chain replacement and/or heavy chain replacement. Chain substitutions for improving antibody affinity are detailed in labeling, antibody affinity maturation by chain substitution, antibody engineering methods and protocols, Humana press (2004) vol.248, pp327-343, which is incorporated herein by reference in its entirety-specifically, light chain substitutions are described in detail in sections 3.1 and 3.2 thereof. In light chain replacement, the heavy chain variable region of the antibody is combined with all light chain variable region partners to identify new VL/VH combinations with high affinity for the target protein of interest. In this way, the antibody/fragment is optimized for very high binding affinity.

In some aspects, the antibodies/fragments of the invention comprise the CDRs (i.e., CDRs 1-3) of the VH and/or VL domains of an IL-11 binding antibody clone described herein, or variants thereof. In some embodiments, the antibodies/fragments of the invention comprise HC-CDR1-3 of an IL-11 binding antibody clone described herein or a variant thereof. In some embodiments, the antibodies/fragments of the invention comprise the LC-CDR1-3 of an IL-11 binding antibody clone described herein or a variant thereof.

HC-CDR1-3 and LC-CDR1-3 of the antibody clones of the invention are defined according to VBASE2, e.g., Retter et al, nucleic acids Res. (2005)33(Suppl 1): D671-D674, the entire contents of which are incorporated herein by reference.

As used herein, a variant of a CDR may comprise, for example, 1 or 2 or 3 substitutions in the amino acid sequence of the CDR. As used herein, a variant of a VL or VH domain may comprise, for example, 1, 2, 3, 4, 5,6, 7, 8, 9, or 10 substitutions in the amino acid sequence of the domain.

In some embodiments, the antibodies/fragments of the invention comprise HC-CDR1-3 of an antibody clone that binds IL-11, or a variant thereof, as described herein, and LC-CDR1-3 of an antibody clone that binds IL-11, or a variant thereof, as described herein.

In some aspects, the antibodies/fragments of the invention comprise the CDRs of the VH and/or VL domains of the antibody clones that bind IL-11 described herein, or variants thereof. In some aspects, the antibodies/fragments of the invention comprise the VH and/or VL domains of an antibody clone that binds IL-11 described herein, or variants thereof.

In some aspects, the antibodies/fragments of the invention comprise CDRs of cloned VH and/or VL domains, or variants thereof, selected from YU-A, YU-B/H, YU-B/YU-G/A, YU-E, YU-E, YU-C/A, YU-D/F, YU-E/E, YU-H/D, YU-A/G, YU-G, YU-B, YU-C/A/B, YU-D/H/C/F/C/E/C/G/H/A, YU-B, YU-E, YU-C/E, YU-F, YU-G/H, YU-H, YU45-F9, YU45-H10, YU46-A10, YU45-F2, YU45-H3, YU45-A1, YU45-A8/C6, YU45-B5/A4, YU45-C3/A6, YU45-D1, YU 1-D1/D1, YU 1-E1, YU 1-G1, YU 1-B1, YU 1-H1, YU 1-B1, YU 1-D1, YU 1-E1, YU 1-F1, YU 1-H1/B1, YU 1-B1, YU 1-B1, YU 1-C1, YU 1-E1, YU 1-C1, YU 1-Y1, YU 1-E1, YU 1-C1, YU 1-E1, YU 1-B1, YU 1-1, YU 1-1, YU 1-; for example, selected from YU45-C11/A10, YU45-G1, YU45-E3, YU45-F8, YU45-F9, YU45-H10, YU45-F2, YU45-H3, YU45-G7, YU45-B6, YU45-C1, YU46-B6, YU46-E3, YU46-G8 or YU 46-D3; or selected from YU33-B4/YU45-G2/A3, YU45-H11/D12, YU45-G1, YU45-D2/H2/C7/F3/C9/E1/E9/C10/G3/H9/C5/A2/A5, YU45-B3, YU45-F8, YU45-H10, YU46-A10, YU45-A8/C6, YU45-D9/D3, YU45-B6, YU45-C1, YU46-A8, YU46-C1, YU46-H8, YU 8-G8-D8 or YU 8-8; or selected from YU33-B4/YU45-G2/A3, YU45-E3, YU45-F2, YU45-F5, YU46-A8 or YU 46-G8.

In some aspects, the antibodies/fragments of the invention comprise a cloned VH and/or VL domain, or variant thereof, selected from the group consisting of YU33-A2, YU33-B3/H3, YU33-B4/YU45-G2/A3, YU33-E3, YU33-E6, YU45-C11/A10, YU45-D11/F11, YU45-E11/E12, YU45-H11/D12, YU45-A12/G10, YU45-G1, YU45-B2, YU 45-C2/A2/B2, YU 2-D2/H2/C2/F2/C2/E2/E2/C2/E2/E2, YU 2-Y2/E2/E2, YU 2-C2/E2/E2, YU 2/E2/E2, YU 2/E2, YU 2/E2, YU 2/E2, YU45-F9, YU45-H10, YU46-A10, YU45-F2, YU45-H3, YU45-A1, YU45-A8/C6, YU45-B5/A4, YU45-C3/A6, YU45-D1, YU 1-D1/D1, YU 1-E1, YU 1-G1, YU 1-B1, YU 1-H1, YU 1-B1, YU 1-D1, YU 1-E1, YU 1-F1, YU 1-H1/B1, YU 1-B1, YU 1-B1, YU 1-C1, YU 1-E1, YU 1-C1, YU 1-Y1, YU 1-E1, YU 1-C1, YU 1-E1, YU 1-B1, YU 1-1, YU 1-1, YU 1-; for example, selected from YU45-C11/A10, YU45-G1, YU45-E3, YU45-F8, YU45-F9, YU45-H10, YU45-F2, YU45-H3, YU45-G7, YU45-B6, YU45-C1, YU46-B6, YU46-E3, YU46-G8 or YU 46-D3; or selected from YU33-B4/YU45-G2/A3, YU45-H11/D12, YU45-G1, YU45-D2/H2/C7/F3/C9/E1/E9/C10/G3/H9/C5/A2/A5, YU45-B3, YU45-F8, YU45-H10, YU46-A10, YU45-A8/C6, YU45-D9/D3, YU45-B6, YU45-C1, YU46-A8, YU46-C1, YU46-H8, YU 8-G8-D8 or YU 8-8; or selected from YU33-B4/YU45-G2/A3, YU45-E3, YU45-F2, YU45-F5, YU46-A8 or YU 46-G8.

In some aspects, the antibodies/fragments of the invention comprise the CDRs of cloned VH and/or VL domains, or variants thereof, selected from BSN-1H2, BSN-1H7, BSN-2E1, BSN-2F5, BSN-2G6, BSN-3C6, BSN-3C11, BSN-5A6, BSN-5B8, BSN-5F6, BSN-6F3, BSN-7D4, BSN-7E4, BSN-7F9, BSN-8C4 or BSN-8H11, for example selected from one of BSN-2E1, BSN-2G6, BSN-3C6, BSN-5A6 or BSN-5B 8; or one selected from BSN-2G6, BSN-3C6, BSN-5B8 or BSN-7D 4; or BSN-3C 6.

In some aspects, the antibodies/fragments of the invention comprise a cloned VH and/or VL domain, or variant thereof, selected from BSN-1H2, BSN-1H7, BSN-2E1, BSN-2F5, BSN-2G6, BSN-3C6, BSN-3C11, BSN-5A6, BSN-5B8, BSN-5F6, BSN-6F3, BSN-7D4, BSN-7E4, BSN-7F9, BSN-8C4 or BSN-8H11, for example selected from one of BSN-2E1, BSN-2G6, BSN-3C6, BSN-5A6 or BSN-5B 8; or one selected from BSN-2G6, BSN-3C6, BSN-5B8 or BSN-7D 4; or BSN-3C 6.

In some aspects, the antibodies/fragments of the invention comprise HC-CDR1-3 of the VH domain of an IL-11 binding antibody clone described herein, or a variant thereof. In some aspects, the antibodies/fragments of the invention comprise a cloned VH domain or variant thereof.

In some aspects, the antibodies/fragments of the invention comprise the LC-CDR1-3 of the VL domain of an IL-11 binding antibody clone described herein, or a variant thereof. In some aspects, the antibodies/fragments of the invention comprise a cloned VL domain or variant thereof.

In some embodiments, an antibody/fragment of the invention comprises a peptide selected from the group consisting of YU33-A2, YU33-B3/H3, YU33-B4/YU45-G2/A3, YU33-E3, YU33-E6, YU45-C11/A10, YU45-D11/F11, YU45-E11/E12, YU45-H11/D12, YU45-A12/G10, YU 10-G10, YU 10-B10, YU 10-C10/A10/B10, YU 10-D10/H10/C10/F10/C10/E10/E10/C10/G10/H10/C10/E10/E10/C10/E10/Y10, YU 10/E10, YU 10-Y10/E10, YU 10/E10, YU 10-Y10/E10, YU 10/E10, YU, binding domains of YU45-F2, YU45-H3, YU45-A1, YU45-A8/C6, YU45-B5/A4, YU45-C3/A6, YU45-D1, YU45-D9/D3, YU45-E5, YU45-G7, YU45-B4, YU45-H4, YU 4-B4, YU 4-D4, YU 4-E4, YU 4-F4, YU 4-H4/B4, YU 4-B4, YU 4-C4, YU 4-G4, YU 4-A4, YU 4-A4-H68672, YU 4672-C5872-A4, YU 4-C4-D4, YU 4-H4, YU 4-B4, YU 4-C4, YU; for example, selected from YU45-C11/A10, YU45-G1, YU45-E3, YU45-F8, YU45-F9, YU45-H10, YU45-F2, YU45-H3, YU45-G7, YU45-B6, YU45-C1, YU46-B6, YU46-E3, YU46-G8 or YU 46-D3; or selected from YU33-B4/YU45-G2/A3, YU45-H11/D12, YU45-G1, YU45-D2/H2/C7/F3/C9/E1/E9/C10/G3/H9/C5/A2/A5, YU45-B3, YU45-F8, YU45-H10, YU46-A10, YU45-A8/C6, YU45-D9/D3, YU45-B6, YU45-C1, YU46-A8, YU46-C1, YU46-H8, YU 8-G8-D8 or YU 8-8; or selected from YU33-B4/YU45-G2/A3, YU45-E3, YU45-F2, YU45-F5, YU46-A8 or YU 46-G8. In some embodiments, the antibody/fragment comprises a VL domain obtained after a light chain substitution.

In some embodiments, an antibody/fragment of the invention comprises a peptide selected from the group consisting of YU33-A2, YU33-B3/H3, YU33-B4/YU45-G2/A3, YU33-E3, YU33-E6, YU45-C11/A10, YU45-D11/F11, YU45-E11/E12, YU45-H11/D12, YU45-A12/G10, YU 10-G10, YU 10-B10, YU 10-C10/A10/B10, YU 10-D10/H10/C10/F10/C10/E10/E10/C10/G10/H10/C10/E10/E10/C10/E10/Y10, YU 10/E10, YU 10-Y10/E10, YU 10/E10, YU 10-Y10/E10, YU 10/E10, YU, binding domains of YU45-F2, YU45-H3, YU45-A1, YU45-A8/C6, YU45-B5/A4, YU45-C3/A6, YU45-D1, YU45-D9/D3, YU45-E5, YU45-G7, YU45-B4, YU45-H4, YU 4-B4, YU 4-D4, YU 4-E4, YU 4-F4, YU 4-H4/B4, YU 4-B4, YU 4-C4, YU 4-G4, YU 4-A4, YU 4-A4-H68672, YU 4672-A4, YU 4672-C5872-A4-D4, YU 4-H4, YU 4-B4, YU 4-L4, YU 4-L4, YU 4-; for example, selected from YU45-C11/A10, YU45-G1, YU45-E3, YU45-F8, YU45-F9, YU45-H10, YU45-F2, YU45-H3, YU45-G7, YU45-B6, YU45-C1, YU46-B6, YU46-E3, YU46-G8 or YU 46-D3; or selected from YU33-B4/YU45-G2/A3, YU45-H11/D12, YU45-G1, YU45-D2/H2/C7/F3/C9/E1/E9/C10/G3/H9/C5/A2/A5, YU45-B3, YU45-F8, YU45-H10, YU46-A10, YU45-A8/C6, YU45-D9/D3, YU45-B6, YU45-C1, YU46-A8, YU46-C1, YU46-H8, YU 8-G8-D8 or YU 8-8; or selected from YU33-B4/YU45-G2/A3, YU45-E3, YU45-F2, YU45-F5, YU46-A8 or YU 46-G8. In some embodiments, the antibody/fragment comprises a VH domain obtained following heavy chain replacement.

The amino acid sequence of VL domain of human anti-human IL-11 binding antibody clone is YU33-A2, YU33-B3/H3, YU33-B4/YU45-G2/A3, YU33-E3, YU33-E6, YU45-C11/A10, YU45-D11/F11, YU45-E11/E12, YU45-H11/D12, YU45-A12/G10, YU45-G1, YU 1-B1, YU 1-C1/A1/B1, YU 1-D1/H1/C1/F1/C1/E1/E1/C1/B1, YU 1-C1/E1/Y1/E1, YU 1-C1/E1/Y1, YU 1-C1/E1, YU 1-Y1, YU 1-E1-1, YU 1-Y1-Y1/E1, YU 1-Y1, YU 1-Y36, YU46-A10, YU45-F2, YU45-H3, YU45-A1, YU45-A8/C6, YU45-B5/A4, YU45-C3/A6, YU45-D1, YU45-D9/D3, YU45-E5, YU45-G7, YU 7-B7, YU 7-H7, YU 7-B7, YU 7-B7, YU 7-D7, YU 7-E7, YU 7-F7, YU 7-H7/B7, YU 7-B7, YU 7-C7, YU 7-G7, YU 7-A7-F7, YU 7-B7, YU 7-B7, YU 7-B7, YU 7-7, YU 7-36, nucleic acids sres (2005)33(suppl 1): D671-D674). The amino acid sequence of the VH domain of these human anti-human IL-11 binding antibody clones is shown in FIG. 16, as HC-CDR1-3 as defined using VBASE 2.

In some aspects, the antibodies/fragments of the invention comprise CDRs of cloned VH and/or VL domains, or variants thereof, selected from YU100-A, YU100-A, YU100-A, YU100-B, YU100-B, YU100-B, YU100-B, YU100-B, YU100-B, YU100-B, YU100-C, YU100-C, YU100-C, YU100-C, YU100-C, YU100-C, YU100-D, YU100-D, YU100-D, YU100-D, YU100-D, YU100-E, YU100-E, YU100-E, YU100-E, YU100-E, YU100-E, YU100-E, YU100-E, YU100-E, YU100-E, YU100-E, YU100-F, YU100-F, YU100-D, YU100-D, YU100-D, YU100-D, YU100-D, YU100-E, YU100-F11, YU100-G01, YU100-G07, YU100-G08, YU100-G09, YU100-G10, YU100-G11, YU100-H01, YU100-H02, YU100-H04, YU100-H05, YU100-H06, YU100-H09, YU100-H11, YU112-A07, YU112-B06, YU112-C03, YU112-C05, YU112-C09, YU112-D08, YU112-E07, YU112-E08, YU112-F05, YU112-G01, YU112-G06, YU112-G09, YU112-H01 or YU 112-H02. The amino acid sequences of the VL domain and LC-CDR1-3 (defined by VBASE 2) for these human anti-human IL-11 binding antibody clones are shown in FIG. 44, and the amino acid sequences of the VH domain and HC-CDR1-3 (defined by VBASE 2) for these human anti-human IL-11 binding antibody clones are shown in FIG. 45.

Antibodies of the invention may comprise VL and/or VH chains comprising amino acid sequences having a high percentage of sequence identity to one or more of the VL and/or VH amino acid sequences described herein. For example, antibodies of the invention include antibodies that bind IL-11 and have a VL chain comprising an amino acid sequence having at least 70%, more preferably at least 75%, 80%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99% or 100% sequence identity to the amino acid sequence of a VL chain of one of SEQ ID nos. 1-50. The antibodies of the invention include antibodies that bind IL-11 and have a VH chain comprising an amino acid sequence having an amino acid sequence with at least 70%, more preferably at least 75%, 80%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% sequence identity to the amino acid sequence of a VH chain of one of SEQ ID nos. 51-100.

The antibodies of the invention include antibodies that bind IL-11 and have a VL chain comprising a heavy chain that is identical to SEQ ID NOs: 267. 269, 270, 271, 274, 277, 279, 280, 540, 283, 286, 287, 289, 353, 293, 297, 299, 301, 303, 305, 307, 309, 310, 312, 314, 316, 318, 319, 321, 323, 325, 327, 328, 329, 331, 332, 335, 337, 338, 341, 342, 343, 346, 348, 214, 350, 13, 3, 351, 355, 358, 35, 361, 363, 365, 366, or 20 has an amino acid sequence with at least 70%, more preferably at least 75%, 80%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% sequence identity. The antibodies of the invention include an amino acid sequence that binds IL-11 and has a VH chain comprising at least 70%, more preferably at least 75%, 80%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99% or 100% sequence identity to the VH chain amino acid sequence of one of SEQ ID nos 53, 368, 369, 370, 371, 372, 373, 374, 375, 377, 378, 379, 380, 382, 383, 384, 385, 386, 387, 388, 389, 85, 390, 73, 391 or 392.

In some embodiments, the antibodies/fragments of the invention comprise an antibody selected from BSN-2E1, BSN-3C6, BSN-5a6_1BSN-2G6, BSN-5a6_2, or BSN-5B 8; IL-11, e.g., BSN-3C6, binds to the VH domain of an antibody clone or the HC-CDR1-3 of the VH domain.

In some embodiments, the antibodies/fragments of the invention comprise an antibody selected from BSN-2E1, BSN-3C6, BSN-5a6_1BSN-2G6, BSN-5a6_2, or BSN-5B 8; for example, IL-11 of BSN-3C6 binds to the VL domain of an antibody clone or the LC-CDR1-3 of the VL domain.

FIG. 68 shows the amino acid sequences of the VH domains of anti-human IL-11 binding antibody clones BSN-2E1, BSN-3C6, BSN-5A 6-1 BSN-2G6, BSN-5A 6-2 and BSN-5B 8. HC-CDR1-3 as defined using VBASE2 (described in Retter et al, Nucl. acids Res. (2005)33(suppl 1): D671-D674). The amino acid sequence of the VL domain of these anti-human IL-11 binding antibody clones is shown in FIG. 69, as defined using VBASE2 for LC-CDR 1-3.

In some aspects, the antibodies/fragments of the invention comprise the CDRs of the VH and/or VL domain of a clone or variant thereof, selected from BSN-2E1, BSN-3C6, BSN-5A6_1BSN-2G6, BSN-5A6_2 or BSN-5B 8; such as BSN-3C 6.

The antibodies of the invention include antibodies that bind IL-11 and have a VL chain comprising a heavy chain that is identical to SEQ ID NOs: 554. 557, 561 or 564 has an amino acid sequence which has at least 70%, more preferably at least 75%, 80%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99% or 100% sequence identity to the VL chain amino acid sequence. The antibodies of the invention include antibodies that bind IL-11 and have a VH chain comprising an amino acid sequence substantially identical to SEQ ID NOs: 541,545,548 or 551, and more preferably, at least 75%, 80%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% sequence identity.

The light and heavy chain CDRs disclosed herein can also be used specifically to bind to a number of different framework regions. Thus, light and/or heavy chains having LC-CDR1-3 or HC-CDR1-3 can have alternative framework regions. Suitable framework regions are well known in the art and are described, for example, in m.lefranc and g.le: franc (2001) "immunoglobulin Books", academic Press, incorporated herein by reference.

The antibodies of the invention may be detectably labeled or at least capable of detection. For example, the antibody may be labeled with a radioactive atom or a colored or fluorescent molecule or a molecule that can be easily detected in any other way. Suitable detectable molecules include fluorescent proteins, luciferases, enzyme substrates, radioactive labels and binding moieties. The label may be by conjugation to an antibody/fragment. The antigen binding molecule may be directly labeled with a detectable label or may be indirectly labeled. In some embodiments, the label may be selected from: radionucleotides, positron emitting radionuclides (e.g. for Positron Emission Tomography (PET)), MRI contrast agents or fluorescent labels.

The antibodies and antigen-binding fragments of the invention may be conjugated to a drug moiety, e.g., a cytotoxic small molecule. Such conjugates can be used for targeted killing of cells expressing the antigenic molecule.

The invention also provides isolated heavy chain variable region polypeptides and isolated light chain variable region polypeptides.

In some aspects, an isolated heavy chain variable region polypeptide is provided that includes the HC-CDR1-3 of any of the anti-IL-11 antibody clones described herein. In some aspects, an isolated heavy chain variable region polypeptide is provided comprising an amino acid sequence having at least 70%, more preferably at least 75%, 80%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99% or 100% sequence identity to the amino acid sequence of the heavy chain variable region of any one of the anti-IL-11 antibody clones described herein.

In some aspects, an isolated light chain variable region polypeptide is provided comprising the LC-CDR1-3 of any one of the anti-IL-11 antibody clones described herein. In some aspects, an isolated light chain variable region polypeptide is provided comprising an amino acid sequence having at least 70%, more preferably at least 75%, 80%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99% or 100% sequence identity to the amino acid sequence of the light chain variable region of any one of the anti-IL-11 antibody clones described herein.

Antibodies of the invention include antibodies that bind IL-11 and comprise an amino acid sequence that has at least 70%, more preferably at least 75%, 80%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99% or 100% sequence identity to the amino acid sequence of one of SEQ ID NOs: 412-475.

Functional Properties of antibodies/fragments

The IL-11 antibodies and fragments of the invention can be characterized by reference to certain functional properties. In particular, an IL-11 antibody or antigen-binding fragment of the invention may have one or more of the following properties:

a) specifically bind to IL-11 (e.g., human IL-11 and/or mouse IL-11);

b) binds to IL-11 (e.g., human IL-11) with a binding affinity of EC50 of less than 1000ng/ml, e.g., as determined by ELISA;

c) inhibiting the interaction between IL-11 and IL-11 Ra;

d) inhibiting the interaction between IL-11 and gp 130;

e) inhibition of IL-11 and IL-11R α: the interaction between gp130 receptor complexes;

f) inhibition of IL-11: the interaction between the IL-11Ra complex and gp 130;

g) inhibition of IL-11 mediated signaling;

h) by IL-11 with IL-11R α: inhibition of signal transduction mediated by binding of the gp130 receptor complex;

i) by IL-11: the binding of the IL-11Ra complex to gp130 (i.e., IL-11 trans signaling) mediates inhibition of signaling;

j) inhibiting fibroblast proliferation;

k) inhibition of myofibroblast production by fibroblasts;

l) inhibition of pathological processes mediated by IL-11;

m) inhibiting fibrosis;

n) inhibits gene or protein expression in fibroblasts of one or more of collagen, fibronectin, periostin, IL-6, IL-11, α SMA, TIMP1, MMP2, e.g., following stimulation with a profibrotic factor.

o) fibroblast inhibition of extracellular matrix production

p) inhibiting proliferation and/or survival of cancer cells;

q) inhibiting tumor growth.

Herein, "inhibit" refers to a decrease, or alleviation relative to a control condition. For example, inhibition of a process by an antibody/fragment refers to a reduction, reduction or lessening of the extent/grade of the process in the absence of the antibody/fragment and/or in the presence of an appropriate control antibody/fragment.

Inhibition may also be referred to herein as neutralization or antagonism. That is, an IL-11 binding antibody/fragment capable of inhibiting a function or process (e.g., an interaction, signaling or other activity mediated by IL-11 or a complex containing IL-11) may be said to be a "neutralizing" or "antagonist" antibody/fragment, related to the function or process involved. For example, an antibody/fragment capable of inhibiting IL-11 mediated signaling may be referred to as an antibody/fragment capable of neutralizing IL-11 mediated signaling, or may be referred to as an antagonist of IL-11 mediated signaling.

The skilled person is able to identify suitable control conditions for a given assay. For example, the control antibody/fragment can be an antibody/fragment directed against a target protein that is known not to have an effect on the property being studied in the assay. The control antibody/fragment may be of the same isotype as the anti-IL-11 antibody/fragment being assayed and may, for example, have the same constant region.

An antibody/fragment that specifically binds a target molecule preferably binds the target with greater affinity and/or for a longer duration than it binds other non-target molecules. In some embodiments, the antibodies/fragments of the invention can bind to IL-11 with greater affinity than one or more members of the IL-6 cytokine family. In some embodiments, the antibodies/fragments of the invention may bind to IL-11 with greater affinity than one or more of IL-6, Leukemia Inhibitory Factor (LIF), oncostatin M (OSM), cardiotrophin-1 (CT-1), ciliary neurotrophic factor (CNTF) and cardiotrophin-like cytokine (CLC).

In some embodiments, the degree of binding of the antibody to the non-target is less than about 10% of the binding of the antibody to the target, as determined by ELISA, SPR, biolayer interferometry (BLI), Microcalorimetry (MST), or by Radioimmunoassay (RIA). Alternatively, binding specificity may be reflected in binding affinity, where the anti-IL-11 antibodies/fragments of the invention bind to the K of IL-11_DAt least 0.1 orders of magnitude (i.e., 0.1 × 10)ⁿWhere n is an integer representing an order of magnitude) greater than K towards another non-target molecule_D. This may optionally be at least one of 0.2,0.3,0.4,0.5,0.6,0.7,0.8,0.9,1.0,1.5 or 2.0.

The binding affinity of an antibody or antigen-binding fragment to its target is generally in terms of its dissociation constant (K)_D) To describe. Binding affinity can be measured by Methods known in the art, such as by ELISA, surface plasmon resonance (SPR; see, e.g., Hearty et al, Methods Mol Biol (2012) 907: 411-.

In some embodiments, the antibodies/fragments of the invention are at a K of 5 μ M or less_DIL-11 is bound, preferably at most 1. mu.M,. ltoreq.500 nM,. ltoreq.100 nM,. ltoreq.75 nM,. ltoreq.50 nM,. ltoreq.40 nM,. ltoreq.30 nM,. ltoreq.20 nM,. ltoreq.15 nM,. ltoreq.12.5 nM,. ltoreq.10 nM,. ltoreq.9 nM,. ltoreq.8 nM,. ltoreq.7 nM,. ltoreq.6 nM,. ltoreq.5 nM,. ltoreq.4 nM. ltoreq.3 nM,. ltoreq.2 nM,. ltoreq.1 nM,. ltoreq.500 pM.

In some embodiments, an antibody/fragment of the invention binds IL-11 with a binding affinity of EC50 (e.g., as determined by ELISA) of 1000ng/ml or less, preferably less than or equal to 900ng/ml, < 800ng/ml, < 700ng/ml, < 600ng/ml, < 500ng/ml, < 400ng/ml, < 300ng/ml, < 200ng/ml, < 100ng/ml, < 90ng/ml, < 80ng/ml, < 70ng/ml, < 60ng/ml, < 50ng/ml, < 40ng/ml, < 30ng/ml, < 20ng/ml, < 15ng/ml, < 10ng/ml, < 7.5ng/ml, < 5ng/ml, < 2.5ng/ml, or < 1 ng/ml.

The affinity of the antibody/fragment for binding to IL-11 can be analyzed in vitro by ELISA assays. Suitable assays are well known in the art and can be performed by the skilled person, e.g. as antibody engineering, volume 1 (2 nd edition), the schpringer protocol, schpringer (2010), Part V, pp 657-665. For example, the affinity of the antibodies/fragments for binding to IL-11 can be analyzed according to the methods described herein in the experimental examples.

The ability of an antibody/fragment to inhibit the interaction between two proteins can be determined, for example, by assaying the interaction in the presence of or after incubation of one or both of the interaction pairs with the antibody/fragment. An example of a suitable assay to determine whether a given antibody/fragment is capable of inhibiting the interaction between two interacting pairs is a competition ELISA assay.

Antibodies/fragments capable of inhibiting a given interaction (e.g., between IL-11 and IL-11Ra, or between IL-11 and gp130, or between IL-11 and IL-11 Ra: gp130, or IL-11: IL-11Ra and gp 130) are identified by observing a reduction/decrease in the level of interaction between the interaction pairs, as compared to the level of interaction in the absence of the antibody/fragment (or in the presence of a suitable control antibody/fragment), in the presence of or after incubation of one or both of the interaction pairs with the antibody/fragment. Suitable assays may be performed in vitro, for example, using recombinant interaction pairs or using cells expressing interaction pairs. The cell expressing the interaction pair may do so endogenously or may do so from a nucleic acid introduced into the cell. For the purposes of such assays, one or both of the interaction pairs and/or antibodies/fragments may be labeled or used in conjunction with a detectable entity to detect and/or determine the level of interaction.

The ability of an antibody/fragment to inhibit the interaction between two binding pairs can also be determined by assaying this interaction, for example, the downstream functional consequences of receptor signaling. For example, IL-11 and IL-11R α: gp130 or IL-11: downstream functional consequences of the interaction between IL-11Ra and gp130 may include fibroblast proliferation, fibroblast production of myofibroblasts, or gene or protein expression of one or more of collagen, fibronectin, periostin, IL-6, IL-11, aSMA, TIMP1, MMP 2.

The fibroblasts of the invention can be derived from any tissue, including liver, lung, kidney, heart, blood vessels, eye, skin, pancreas, spleen, intestine (e.g., large or small intestine), brain, and bone marrow. In particular embodiments, for analysis of antibodies/fragments, the fibroblast may be a cardiac fibroblast (e.g., an atrial fibroblast), a skin fibroblast, a lung fibroblast, a kidney fibroblast, or a liver fibroblast. Fibroblasts may be characterized by gene or protein expression of one or more of COL1A, ACTA2, prolyl-4-hydroxylase, MAS516 and FSP 1.

Gene expression can be determined by various methods known to those skilled in the art, for example by quantitative real-time PCR (qRT-PCR) or by reporter-based methods to determine mRNA levels. Similarly, protein expression can be determined by various methods well known in the art, for example, by antibody-based methods, such as by western blotting, immunohistochemistry, immunocytochemistry, flow cytometry, ELISA, ELISPOT, or reporter-based methods.

In some embodiments, the antibodies/fragments of the invention can inhibit protein expression of one or more fibrotic markers, e.g., one or more of collagen, fibronectin, periostin, IL-6, IL-11, α SMA, TIMP1, MMP 2.

The antibodies/fragments inhibit IL-11 and IL-11R α: the ability of gp130 to interact can be analyzed, for example, by stimulating fibroblasts with TGF β 1, incubating the cells in the presence of antibodies/fragments and analyzing the proportion of cells having an α SMA positive phenotype after a defined period of time. In such an example, IL-11 and IL-11R α: inhibition of the interaction between gp130 can be identified by observing a lower proportion of cells with an alpha SMA positive phenotype, compared to positive control conditions in which cells are treated with TGF β 1 in the absence of antibody/fragment (or in the presence of an appropriate control antibody/fragment), or in the presence of an appropriate control antibody/fragment.

Such assays are also useful for assaying the ability of the antibodies/fragments to inhibit IL-11 mediated signaling.

In some embodiments, the antibodies/fragments of the invention are capable of inhibiting the interaction between IL-11 and IL-11ra to less than 100% of the level of interaction between IL-11 and IL-11ra in the absence of the antibody/fragment (or in the presence of a suitable control antibody/fragment), e.g., one of 99% or less, 95% or less, 90% or less, 85% or less, 75% or less, 70% or less, 65% or less, 60% or less, 55% or less, 50% or less, 45% or less, 40% or less, 35% or less, 30% or less, 25% or less, 20% or less, 15% or less, 10% or less, 5% or less, or 1% or less. In some embodiments, the antibodies/fragments of the invention are capable of inhibiting the interaction between IL-11 and IL-11R α to less than 1, e.g., less than or equal to 0.99, less than or equal to 0.95, less than or equal to 0.9, less than or equal to 0.85, less than or equal to 0.8, less than or equal to 0.85, less than or equal to 0.75, less than or equal to 0.7, less than or equal to 0.65, less than or equal to 0.6, less than or equal to 0.55, less than or equal to 0.5, less than or equal to 0.45, less than or equal to 0.4, less than or equal to 0.35, less than or equal to 0.3, less than or equal to 0.25, less than or equal to 0.2, less than or equal to 0.15, less than or equal to one of 0.1 times the level of interaction between IL-11 and IL-11R α in the absence of the antibody.

In some embodiments, the antibodies/fragments of the invention are capable of inhibiting the interaction between IL-11 and gp130 to a level of less than 100%, e.g., one of 99% or less, 95% or less, 90% or less, 85% or less, 75% or less, 70% or less, 65% or less, 60% or less, 55% or less, 50% or less, 45% or less, 40% or less, 35% or less, 30% or less, 25% or less, 20% or less, 15% or less, 10% or less, 5% or less, or 1% less of the interaction between IL-11 and gp130 in the absence of the antibody/fragment (or in the presence of an appropriate control antibody/fragment). In some embodiments, the antibodies/fragments of the invention are capable of inhibiting the interaction between IL-11 and gp130 to less than 1 times, e.g., less than or equal to 0.99 times, less than or equal to 0.95 times, less than or equal to 0.9 times, less than or equal to 0.85 times, less than or equal to 0.8 times, less than or equal to 0.85 times, less than or equal to 0.75 times, less than or equal to 0.7 times, less than or equal to 0.65 times, less than or equal to 0.6 times, less than or equal to 0.55 times, less than or equal to 0.5 times, less than or equal to 0.45 times, less than or equal to 0.4 times, less than or equal to 0.35 times, less than or equal to 0.3 times, less than or equal to 0.25 times, less than or equal to 0.2 times, less than or equal to 0.15 times, less than or equal to 0.1 times of the interaction between IL-11 and gp130 in the absence of.

In some embodiments, the antibodies/fragments of the invention are capable of inhibiting IL-11 and IL-11R α: interaction between gp130 to IL-11 and IL-11R α in the absence of antibody/fragment (or in the presence of an appropriate control antibody/fragment): less than 100% of the level of interaction between gp130, e.g., one of 99% or less, 95% or less, 90% or less, 85% or less, 75% or less, 70% or less, 65% or less, 60% or less, 55% or less, 50% or less, 45% or less, 40% or less, 35% or less, 30% or less, 25% or less, 20% or less, 15% or less, 10% or less, 5% or less, or 1% or less. In some embodiments, the antibodies/fragments of the invention are capable of inhibiting IL-11 and IL-11R α: interaction between gp130 to IL-11 and IL-11R α in the absence of antibody/fragment (or in the presence of an appropriate control antibody/fragment): the level of interaction between gp130 is less than 1, e.g. less than or equal to 0.99, less than or equal to 0.95, less than or equal to 0.9, less than or equal to 0.85, less than or equal to 0.8, less than or equal to 0.85, less than or equal to 0.75, less than or equal to 0.7, less than or equal to 0.65, less than or equal to 0.6, less than or equal to 0.55, less than or equal to 0.5, less than or equal to 0.45, less than or equal to 0.4, less than or equal to 0.35, less than or equal to 0.3, less than or equal to 0.25, less than or equal to 0.2, less than or equal to 0.15, less than or equal to one of 0.1.

In some embodiments, the antibodies/fragments of the invention are capable of inhibiting IL-11: the interaction between the IL-11ra complex and gp130 to IL-11 in the absence of antibody/fragment (or in the presence of an appropriate control antibody/fragment): less than 100%, e.g., one of 99% or less, 95% or less, 90% or less, 85% or less, 75% or less, 70% or less, 65% or less, 60% or less, 55% or less, 50% or less, 45% or less, 40% or less, 35% or less, 30% or less, 25% or less, 20% or less, 15% or less, 10% or less, 5% or less, or 1% or less of the level of interaction between the IL-11ra complex and gp 130. In some embodiments, the antibody/fragment is capable of inhibiting IL-11: interaction between the IL-11R α complex and gp130 to IL-11 in the absence of antibody/fragment: less than 1 times, e.g., less than or equal to 0.99 times, less than or equal to 0.95 times, less than or equal to 0.9 times, less than or equal to 0.85 times, less than or equal to 0.8 times, less than or equal to 0.85 times, less than or equal to 0.75 times, less than or equal to 0.7 times, less than or equal to 0.65 times, less than or equal to 0.6 times, less than or equal to 0.55 times, less than or equal to 0.5 times, less than or equal to 0.45 times, less than or equal to 0.4 times, less than or equal to 0.35 times, less than or equal to 0.3 times, less than or equal to 0.25 times, less than or equal to 0.2 times, less than or equal to 0.15 times, less than or equal to 0.1 times the level of.

Inhibition of IL-11 mediated signaling may also be used³H-thymidine incorporation and/or Ba/F3 cell proliferation assays, for example, as described in, e.g., Curtis et al, blood, 1997, 90(11), and Karpovich et al, mol.hum.reprod.20039 (2): 75-80.Ba/F3 cells co-express IL-11Ra and those described in gp 130.

As used herein, IL-11-mediated signaling and/or processes mediated by IL-11 include signaling mediated by IL-11 fragments and polypeptide complexes comprising IL-11 or fragments thereof. IL-11 mediated signaling can be signaling mediated by human IL-11 and/or mouse IL-11. IL-11 mediated signaling can occur upon binding of IL-11 or a complex containing IL-11 to IL-11 or a receptor to which the complex binds.

In some embodiments, the antibodies and fragments of the invention are capable of inhibiting the biological activity of IL-11 or a complex comprising IL-11. In some embodiments, the antibody/fragment binds to IL-11 or a complex comprising IL-11 in a region that is important for binding to IL-11 or a complex comprising IL-11, e.g., a receptor for gp130 or IL-11Ra, thereby disrupting binding to and/or signaling through the receptor.

In some embodiments, the antibodies/fragments of the invention are antagonists of one or more signaling pathways that are mediated by a protein comprising IL-11R α and/or gp130, e.g., IL-11R α: gp130 receptor is activated by signal transduction. In some embodiments, the antibody/fragment can be produced by one or more antibodies comprising IL-11R α and/or gp130, e.g., IL-11R α: the immunoreceptor complex of gp130 inhibits signaling.

In some embodiments, the antibodies/fragments of the invention are capable of inhibiting IL-11-mediated signaling to less than 100% of the level of signaling in the absence of the antibody/fragment (or in the presence of a suitable control antibody/fragment), e.g., 99% or less, 95% or less, 90% or less, 85% or less, 75% or less, 70% or less, 65% or less, 60% or less, 55% or less, 50% or less, 45% or less, 40% or less, 35% or less, 30% or less, 25% or less, 20% or less, 15% or less, 10% or less, 5% or less, or 1% or less. In some embodiments, the antibody/fragment is capable of reducing IL-11 mediated signaling to less than 1-fold, e.g., less than or equal to 0.99-fold, ≦ 0.95-fold, ≦ 0.9-fold, ≦ 0.85-fold, ≦ 0.8-fold, ≦ 0.85-fold, ≦ 0.75-fold, ≦ 0.7-fold, ≦ 0.65-fold, ≦ 0.6-fold, ≦ 0.55-fold, ≦ 0.5-fold, ≦ 0.45-fold, ≦ 0.4-fold, ≦ 0.35-fold, ≦ 0.3-fold, ≦ 0.25-fold, ≦ 0.2-fold, ≦ 0.15-fold, or ≦ 0.1 of the level of signaling in the absence of the antibody/fragment (or in the presence of an appropriate control antibody/fragment).

In some embodiments, IL-11 mediated signaling can be through interaction of IL-11 with IL-11R α: gp130 receptor binding-mediated signaling. This signaling can be assayed, for example, by treating cells expressing IL-11Ra and gp130 with IL-11, or by stimulating IL-11 production in cells expressing IL-11Ra and gp 130.

IC of antibody/fragment inhibiting IL-11 mediated signaling can be determined₅₀For example, by culturing IL-11R α and gp130 expressing Ba/F3 cells in the presence of human IL-11 and IL-11 binding agents and measuring³H-thymidine is incorporated into DNA.

In some embodiments, the antibodies/fragments of the invention may exhibit an IC of 10 μ g/ml or less in such assays₅₀Preferably not more than 5. mu.g/ml,. ltoreq.4. mu.g/ml,. ltoreq.3.5. mu.g/ml,. ltoreq.3. mu.g/ml,. ltoreq.2. mu.g/ml,. ltoreq.1. mu.g/ml,. ltoreq.0.9. mu.g/ml,. ltoreq.0.8. mu.g/ml,. ltoreq.0.7. mu.g/ml,. ltoreq.0.6. mu.g/ml, or. ltoreq.0.5. mu.g/mlOne of the concentrations of the compound per ml.

In some embodiments, IL-11 mediated signaling can be through IL-11: signaling mediated by the binding of the IL-11R α complex to gp 130. In some embodiments, the ratio of IL-11: the IL-11Ra complex can be soluble, e.g., a complex of IL-11Ra and the extracellular domain of IL-11, or a soluble IL-11Ra isoform/fragment and IL-11. In some embodiments, the soluble IL-11Ra is a soluble (secreted) isoform of IL-11Ra or is a release product of the extracellular domain of IL-11Ra by proteolytic cleavage of the cell membrane.

In some embodiments, the ratio of IL-11: the IL-11Ra complex may be cell-bound, e.g., a complex of cell membrane-bound IL-11Ra and IL-11. By using IL-11: treatment of gp 130-expressing cells with an IL-11Ra complex (e.g., a recombinant fusion protein comprising IL-11 linked to the extracellular domain of IL-11Ra (e.g., superIL-11 as described herein) via a peptide linker) can be assayed for expression of gp130 by IL-11: signaling mediated by the binding of the IL-11R α complex to gp 130.

In some embodiments, the antibodies/fragments of the invention are capable of inhibiting the activity of an antibody produced by IL-11: signaling mediated by the binding of the IL-11ra complex to gp130, and is also capable of inhibiting the binding of gp130 to gp130 by IL-11: gp130 receptor binding-mediated signaling.

In some embodiments, the antibody/fragment is capable of inhibiting fibroblast proliferation. Proliferation of fibroblasts can be determined by analyzing cell division over a period of time. Cell division of a given fibroblast population may be analyzed, for example, by in vitro analysis³Incorporation of H-thymidine or by CFSE dilution assays, e.g., as described by Fulcher and Wong, Immunol Cell Biol (1999)77 (6): 559-564, incorporated herein by reference in its entirety. Proliferating cells (e.g., proliferating fibroblasts) can also be analytically identified by assaying for the incorporation of 5-ethynyl-2' -deoxyuridine (EdU) by an appropriate assay, as described, for example, in Buck et al, biotechnology.2008; 44(7): 927-9, and Sali and Mitchison, PNAS usa, 2008/2/19; 105(7): 2415-2420, both of which are incorporated herein by reference in their entirety.

Fibroblasts of the present disclosure can be derived from any tissue, including liver, lung, kidney, heart, blood vessels, eye, skin, pancreas, spleen, intestine (e.g., large or small intestine), brain, and bone marrow. In particular embodiments, for analysis of antibodies/fragments, the fibroblast may be a cardiac fibroblast (e.g., an atrial fibroblast), a skin fibroblast, a lung fibroblast, a kidney fibroblast, or a liver fibroblast.

In some embodiments, the antibodies/fragments of the invention are capable of inhibiting fibroblast proliferation to less than 100% of the level of fibroblast proliferation in the absence of the antibody/fragment (or in the presence of an appropriate control antibody/fragment), e.g., 99% or less, 95% or less, 90% or less, 85% or less, 75% or less, 70% or less, 65% or less, 60% or less, 55% or less, 50% or less, 45% or less, 40% or less, 35% or less, 30% or less, 25% or less, 20% or less, 15% or less, 10% or less, 5% or less, or 1% or less. In some embodiments, the antibody/fragment is capable of reducing fibroblast proliferation to less than 1 fold in the absence of the antibody/fragment (or in the presence of an appropriate control antibody/fragment), e.g., ≦ 0.99 fold, ≦ 0.95 fold, ≦ 0.9 fold, ≦ 0.85 fold, ≦ 0.8 fold, ≦ 0.85 fold, ≦ 0.75 fold, ≦ 0.7 fold, ≦ 0.65 fold, ≦ 0.6 fold, ≦ 0.55 fold, ≦ 0.5 fold, ≦ 0.45 fold, ≦ 0.4 fold, ≦ 0.35 fold, ≦ 0.3 fold, ≦ 0.25 fold, ≦ 0.2 fold, ≦ 0.15 fold, or ≦ 0.1 fold.

In some embodiments, the antibodies/fragments of the invention are capable of inhibiting IL-11 mediated pathological processes, e.g., following stimulation with a profibrotic factor (e.g., TGF β 1). Pathological processes mediated by IL-11 include fibrosis and can be assessed in vitro or in vivo.

In some embodiments, the antibodies/fragments of the invention are capable of inhibiting fibrosis. Fibrosis may be a specific tissue or several tissues, e.g. liver, lung, kidney, heart, blood vessels, eye, skin, pancreas, spleen, intestine (e.g. large or small intestine), brain or bone marrow. Fibrosis can be measured by methods well known to those skilled in the art, for example by analyzing the gene or protein expression of one or more myofibroblast markers and/or the gene or protein expression of one or more fibrosis markers in a given tissue or tissues.

Myofibroblast markers may include one or more of increased alpha SMA, vimentin, palatinoin (palladin), filaggrin, or myodesmin. Markers of fibrosis include increased levels of collagen, fibronectin, periostin, IL-6, IL-11, α SMA, TIMP1 and MMP2, extracellular matrix components, myofibroblast number/proportion and organ weight.

Inhibition of fibrosis can be measured in vitro or in vivo. For example, one can analyze whether an antibody/fragment is capable of inhibiting fibrosis in a given tissue in vitro by treating fibroblasts from that tissue with a profibrotic stimulus, and then analyze whether the antibody can reduce myofibroblast production (or, for example, some other marker of fibrosis) from the fibroblasts. Whether the antibody/fragment is capable of inhibiting fibrosis can be analyzed in vivo, for example, by administering the antibody/fragment to a subject (e.g., a subject that has been exposed to a profibrotic stimulus) and analyzing the tissue for one or more markers of fibrosis.

In some embodiments, the antibodies/fragments of the invention are capable of inhibiting fibrosis to less than 100% of the level of fibrosis in the absence of the antibody/fragment (or in the presence of an appropriate control antibody/fragment), e.g., one of 99% or less, 95% or less, 90% or less, 85% or less, 75% or less, 70% or less, 65% or less, 60% or less, 55% or less, 50% or less, 45% or less, 40% or less, 35% or less, 30% or less, 25% or less, 20% or less, 15% or less, 10% or less, 5% or less, or 1% or less. In some embodiments, the antibody/fragment is capable of reducing fibrosis to less than 1 times, e.g., ≦ 0.99 times, ≦ 0.95 times, ≦ 0.9 times, ≦ 0.85 times, ≦ 0.8 times, ≦ 0.85 times, ≦ 0.75 times, ≦ 0.7 times, ≦ 0.65 times, ≦ 0.6 times, ≦ 0.55 times, ≦ 0.5 times, ≦ 0.45 times, ≦ 0.4 times, ≦ 0.35 times, ≦ 0.3 times, ≦ 0.25 times, ≦ 0.2 times, ≦ 0.15 times, ≦ 0.1 one of the levels of fibrosis in the absence of the antibody/fragment (or in the presence of an appropriate control antibody/fragment).

In some embodiments, the antibodies/fragments of the invention are capable of inhibiting the production of myofibroblasts from fibroblasts, e.g., after exposing the fibroblasts to a profibrotic factor. The production of myofibroblasts from fibroblasts can be studied by analyzing myofibroblast markers. The profibrotic factor of the present disclosure may be, for example, TGF β 1, IL-11, IL-13, PDGF, ET-1, oncostatin M (OSM), or ANG2 (AngII).

In some embodiments, the antibody/fragment is capable of inhibiting gene or protein expression of one or more of collagen, fibronectin, periostin, IL-6, IL-11, α SMA, TIMP1, MMP2 in a fibroblast or fibroblast-derived cell (e.g., myofibroblast), e.g., upon stimulation with a profibrinolytic factor. In some embodiments, the antibody/fragment is capable of inhibiting gene or protein expression of one or more extracellular matrix components in a fibroblast or fibroblast-derived cell (e.g., myofibroblast), e.g., upon stimulation with a profibrotic factor.

In the experimental examples herein, myofibroblast production from fibroblasts was analyzed by measuring alpha SMA protein expression levels using the Operetta high content imaging system after stimulation of fibroblasts with TGF β 1.

In some embodiments, the antibodies/fragments of the invention are capable of inhibiting less than 100% of the level of myofibroblasts produced from fibroblasts to myofibroblasts produced from fibroblasts in the absence of the antibodies/fragments (or in the presence of a suitable control antibody/fragment), e.g., one of 99% or less, 95% or less, 90% or less, 85% or less, 75% or less, 70% or less, 65% or less, 60% or less, 55% or less, 50% or less, 45% or less, 40% or less, 35% or less, 30% or less, 25% or less, 20% or less, 15% or less, 10% or less, 5% or less, or 1% or less. In some embodiments, the antibody/fragment is capable of reducing myofibroblasts produced from fibroblasts to less than 1, such as less than or equal to 0.99, less than or equal to 0.95, less than or equal to 0.9, less than or equal to 0.85, less than or equal to 0.8, less than or equal to 0.85, less than or equal to 0.75, less than or equal to 0.7, less than or equal to 0.65, less than or equal to 0.6, less than or equal to 0.55, less than or equal to 0.5, less than or equal to 0.45, less than or equal to 0.4, less than or equal to 0.35, less than or equal to 0.3, less than or equal to 0.25, less than or equal to 0.2, less than or equal to 0.15, less than or equal to one of 0.1 in the absence of the antibody/fragment (or the presence of a suitable control antibody/fragment).

In some embodiments, the antibodies/fragments of the invention are capable of inhibiting the expression of one or more of the genes or proteins of collagen, fibronectin, periostin, IL-6, IL-11, α SMA, TIMP1, MMP2 in fibroblasts, e.g., following stimulation with a profibrotic factor (e.g., TGF β 1). In some embodiments, an antibody/fragment of the invention is capable of inhibiting gene or protein expression to less than 100% of the level of gene or protein expression in the absence of the antibody/fragment (or in the presence of a suitable control antibody/fragment), e.g., 99% or less, 95% or less, 90% or less, 85% or less, 75% or less, 70% or less, 65% or less, 60% or less, 55% or less, 50% or less, 45% or less, 40% or less, 35% or less, 30% or less, 25% or less, 20% or less, 15% or less, 10% or less, 5% or less, or 1% or less. In some embodiments, the antibody/fragment is capable of reducing gene or protein expression to one of less than 1-fold, e.g., less than or equal to 0.99-fold, ≦ 0.95-fold, ≦ 0.9-fold, ≦ 0.85-fold, ≦ 0.8-fold, ≦ 0.85-fold, ≦ 0.75-fold, ≦ 0.7-fold, ≦ 0.65-fold, ≦ 0.6-fold, ≦ 0.55-fold, ≦ 0.5-fold, ≦ 0.45-fold, ≦ 0.4-fold, ≦ 0.35-fold, ≦ 0.3-fold, ≦ 0.25-fold, ≦ 0.2-fold, ≦ 0.15-fold, or ≦ 0.1-fold in the absence of the antibody/fragment (or in the presence of a suitable control antibody/fragment).

In some embodiments, the antibodies/fragments of the invention are capable of inhibiting the production of extracellular matrix by fibroblasts, e.g., following stimulation with a profibrotic factor (e.g., TGF β 1). Extracellular matrix production can be assessed, for example, by measuring the levels of extracellular matrix components. Extracellular matrix components of the invention include, for example, proteoglycans, heparan sulfates, chondroitin sulfates, keratan sulfates, hyaluronic acid, collagen, periostin, fibronectin, vitronectin, elastin, fibronectin, laminin, entactin, gelatin, and aggrecan.

In some embodiments, the antibodies/fragments of the invention are capable of inhibiting less than 100% of extracellular matrix produced by fibroblasts to a level of extracellular matrix produced by fibroblasts in the absence of the antibody/fragment (or in the presence of an appropriate control antibody/fragment), e.g., 99% or less, 95% or less, 90% or less, 85% or less, 75% or less, 70% or less, 65% or less, 60% or less, 55% or less, 50% or less, 45% or less, 40% or less, 35% or less, 30% or less, 25% or less, 20% or less, 15% or less, 10% or less, 5% or less, or 1% or less. In some embodiments, the antibody/fragment is capable of reducing extracellular matrix produced by a fibroblast to less than 1-fold, e.g., less than or equal to 0.99-fold, ≦ 0.95-fold, ≦ 0.9-fold, ≦ 0.85-fold, ≦ 0.8-fold, ≦ 0.85-fold, ≦ 0.75-fold, ≦ 0.7-fold, ≦ 0.65-fold, ≦ 0.6-fold, ≦ 0.55-fold, ≦ 0.5-fold, ≦ 0.45-fold, ≦ 0.4-fold, ≦ 0.35-fold, ≦ 0.3-fold, ≦ 0.25-fold, ≦ 0.2-fold, ≦ 0.15-fold, or ≦ 0.1-fold of the level of extracellular matrix produced in the absence of the antibody/fragment (or in the presence of an appropriate control antibody/fragment).

In some embodiments, the antibodies/fragments of the invention are capable of inhibiting the proliferation and/or survival of cancer cells. The skilled artisan is able to determine whether the antibody/fragment is capable of inhibiting the proliferation and/or survival of a cancer cell, for example, by assaying the effect of the antibody/fragment on the cancer cell. For example, proliferation of a cell can be measured as described herein, e.g., by³H thymidine incorporation or CFSE dilution assay. Cell survival can be analyzed by measuring cell viability/cell death markers of cells after treatment with the antibody/fragment.

In some embodiments, the antibodies/fragments of the invention are capable of inhibiting proliferation and/or survival of cancer cells to a level of less than 100% of the proliferation and/or survival of cancer cells in the absence of the antibody/fragment (or in the presence of an appropriate control antibody/fragment), e.g., one of 99% or less, 95% or less, 90% or less, 85% or less, 75% or less, 70% or less, 65% or less, 60% or less, 55% or less, 50% or less, 45% or less, 40% or less, 35% or less, 30% or less, 25% or less, 20% or less, 15% or less, 10% or less, 5% or less, or 1% or less. In some embodiments, the antibody/fragment is capable of reducing proliferation and/or survival of a cancer cell to less than 1 time, e.g., less than or equal to 0.99 times, less than or equal to 0.95 times, less than or equal to 0.9 times, less than or equal to 0.85 times, less than or equal to 0.8 times, less than or equal to 0.85 times, less than or equal to 0.75 times, less than or equal to 0.7 times, less than or equal to 0.65 times, less than or equal to 0.6 times, less than or equal to 0.55 times, less than or equal to 0.5 times, less than or equal to 0.45 times, less than or equal to 0.4 times, less than or equal to 0.35 times, less than or equal to 0.3 times, less than or equal to 0.25 times, less than or equal to 0.2 times, less than or equal to 0.15 times, less than or equal to one of the level of proliferation and/or equal to 0.1 times of a cancer cell.

In some embodiments, the antibodies/fragments of the invention are capable of inhibiting tumor growth to less than 100% of the level of tumor growth in the absence of the antibody/fragment (or in the presence of an appropriate control antibody/fragment), e.g., 99% or less, 95% or less, 90% or less, 85% or less, 75% or less, 70% or less, 65% or less, 60% or less, 55% or less, 50% or less, 45% or less, 40% or less, 35% or less, 30% or less, 25% or less, 20% or less, 15% or less, 10% or less, 5% or less, or 1% or less. In some embodiments, the antibody/fragment is capable of reducing tumor growth to one of less than 1 time, e.g., less than or equal to 0.99 times, less than or equal to 0.95 times, less than or equal to 0.9 times, less than or equal to 0.85 times, less than or equal to 0.8 times, less than or equal to 0.85 times, less than or equal to 0.75 times, less than or equal to 0.7 times, less than or equal to 0.65 times, less than or equal to 0.6 times, less than or equal to 0.55 times, less than or equal to 0.5 times, less than or equal to 0.45 times, less than or equal to 0.4 times, less than or equal to 0.35 times, less than or equal to 0.3 times, less than or equal to 0.25 times, less than or equal to 0.2 times, less than or equal to 0.15 times, less than or equal to 0.1 times the level of tumor growth in the.

In some embodiments, the antibodies/fragments of the invention have one or more improved properties compared to prior art anti-IL-11 antibodies/fragments. In some embodiments, the prior art anti-IL-11 antibody/antigen-binding fragment may be or may comprise the CDR and/or VL and VH sequences of monoclonal mouse anti-human IL-11 antibody clone # 22626. Cat 218(R & D system, MN, usa).

In some embodiments, the antibodies/fragments of the invention exhibit one or more of the following properties compared to prior art antibodies/antigen binding fragments (e.g., monoclonal mouse antibody clone # 22626; cat # MAB 218):

(i) binding to IL-11 is more specific (i.e., reduces cross-reactivity of proteins of the IL-6 cytokine family other than IL-11) relative to one or more of IL-6, LIF, OSM, CT-1, CNTF, and CLC;

(ii) binds IL-11 (e.g., human IL-11) with greater affinity (e.g., lower EC50 as determined by ELISA);

(iii) inhibit the interaction between IL-11 and IL-11R α to a greater extent;

(iv) inhibits the interaction between IL-11 and gp130 to a greater extent;

(v) greater inhibition of IL-11 and IL-11R α: the interaction between gp130 receptor complexes;

(vi) greater inhibition of IL-11: the interaction between the IL-11Ra complex and gp 130;

(vii) inhibits IL-11 mediated signaling to a greater extent;

(viii) greater inhibition of the binding of IL-11 to IL-11R α: gp130 receptor complex binding-mediated signaling;

(ix) more inhibition by IL-11: signaling mediated by the binding of the IL-11Ra complex to gp130 (i.e., IL-11 trans signaling);

(x) Inhibit fibroblast proliferation to a greater extent;

(xi) Inhibit the production of myofibroblasts from fibroblasts to a greater extent;

(xii) (ii) greater inhibition of pathological processes mediated by IL-11;

(xiii) Inhibit fibrosis to a greater extent;

(xiv) Inhibiting gene or protein expression of one or more of collagen, fibronectin, periostin, IL-6, IL-11, α SMA, TIMP1, MMP2 in fibroblasts, e.g., following stimulation with a profibrotic factor to a greater extent;

(xv) Inhibit fibroblast to produce extracellular matrix to a greater extent;

(xvi) Inhibit proliferation and/or survival of cancer cells to a greater extent; or

(xvii) Inhibit tumor growth to a greater extent.

In some embodiments, the "higher specificity" or "greater affinity" or "greater inhibition" herein is greater than 1 time, e.g., greater than 1.01 times, greater than 1.02 times, greater than 1.03 times, greater than 1.04 times, greater than 1.05 times, greater than 1.06 times, greater than 1.07 times, greater than 1.08 times, greater than 1.09 times, greater than 1.1 times, greater than 1.2 times, greater than 1.3 times, greater than 1.4 times, greater than 1.5 times, greater than 1.6 times, greater than 1.7 times, greater than 1.8 times, greater than 1.9 times, greater than 2 times, greater than 2.1 times, greater than 2.2 times, greater than 2.3 times, greater than 2.4 times, greater than 1.5 times, greater than 1.6 times, greater than 1.7 times, greater than 1.8 times, greater than 1.9 times, greater than 2 times greater than 2.5 times, greater than 2.5 times greater than 2 times greater than 5 times greater than 2.5 times greater than 5 times, greater than 2.9 times greater than 2 times greater than 5 times greater than 2.9 times greater than 5 times greater than 2.5 times greater than 2 times greater than 2.9 times greater than 2 times, not less than 30 times, not less than 35 times, not less than 40 times, not less than 45 times, not less than 50 times, not less than 60 times, not less than 70 times, not less than 80 times, not less than 90 times, not less than 100 times, not less than 200 times, not less than 300 times, not less than 400 times, not less than 500 times, not less than 600 times, not less than 700 times, not less than 800 times, not less than 900 times, not less than 1000 times.

Therapeutic applications

The antibodies and antigen-binding fragments of the invention, as well as compositions comprising these agents, may be provided for use in medical treatment methods or to prevent diseases/disorders or to alleviate symptoms of diseases/disorders. The antibodies/fragments of the invention may be administered to a subject having a disease/disorder in need of treatment, and/or to a subject at risk of developing or contracting a disease/disorder.

The treatment, prevention, or amelioration of fibrosis of the invention can be fibrosis associated with upregulation of IL-11 and/or IL-11R α, e.g., upregulation of IL-11 and/or IL-11R α in cells or tissues in which the disease/disorder occurs or is likely to occur, or upregulation of extracellular IL-11 or IL-11R α. In some embodiments, IL-11 or IL-11R expression in the subjects local or systemic upregulation.

Treating or ameliorating the disease/disorder can be effective to prevent the progression of the disease/disorder, e.g., prevent the worsening of the disease or slow the rate of progression. In some embodiments, treatment or amelioration can result in an improvement in the disease/disorder, e.g., a reduction in the symptoms of the disease/disorder or a reduction in the severity/activity of some other related disease/disorder.

Preventing a disease/disorder may refer to preventing worsening of the disorder or preventing the development of the disease/disorder, e.g., preventing the development of an early disease/disorder to a later, chronic stage.

The antibodies/fragments of the invention are preferably capable of binding to and inhibiting the biological activity of IL-11 and IL-11-containing molecules/complexes (e.g., IL-11: IL-11Ra complex). Accordingly, the antibodies/fragments of the invention are useful for treating or preventing diseases and disorders in which IL-11 is associated with the pathology of the disease/disorder. That is, the antibodies/fragments of the invention are useful for treating or preventing diseases and disorders associated with IL-11/IL-11R signaling.

In some embodiments, the disease/disorder can be associated with increased IL-11, IL-11Ra and/or gp130 gene or protein expression, e.g., as compared to a control (i.e., non-diseased) state. In some embodiments, the disease/disorder may be associated with an elevated level of IL-11-mediated signaling compared to a control state. In some embodiments, the disease/disorder may be associated with an increased level of signaling through the ERK and/or STAT3 pathway as compared to a control state. In some embodiments, increased expression/activity of IL-11, IL-11Ra and/or gp130 and/or increased levels of IL-11-mediated signaling can be observed in effector cells (e.g., cancer cells) of a disease/disorder. In some embodiments, increased expression/activity of IL-11, IL-11Ra and/or gp130 and/or increased levels of IL-11-mediated signaling can be observed in cells other than effector cells.

Signaling through ERK can be measured, for example using an assay for ERK phosphorylation, such as the assays described in the assay instruction manual: Phospho-ERK assay, Kim E.Gardison, Beverly A.Heinz, Mary E.Lajiness, Jeffrey R.Weidner and G.Sitta Sittamaparam, Li Lai, Sittamaparam GS, Coissens NP, Nelson H et al, edited by Bethesda (MD): the lilies and the country push forward the center for conversion science; 2004. signaling through STAT3 can be measured, for example, using an assay for phosphorylation of STAT3, such as the Phospho-STAT3(Tyr705) cell assay kit (Cisbio assay).

In some embodiments, the treatment is a disease/disorder, wherein the reduction of IL-11 mediated signaling is therapeutic. In some embodiments, the treatment is a disease/disorder associated with excessive ERK and/or STAT3 signaling. In some embodiments, the treatment is a disease/disorder associated with hyperproliferation or overactivation of fibroblasts, or a disease/disorder associated with an excess of myofibroblasts.

In some embodiments, treatment may be intended to prevent or treat a disease/disorder by reducing the number or proportion of myofibroblasts or alpha SMA positive fibroblasts.

In some embodiments, the disease/disorder may be fibrosis, a fibrotic disorder, or a disease/disorder characterized by fibrosis. As used herein, "fibrosis" refers to the formation of excess fibrous connective tissue due to excessive deposition of extracellular matrix components (e.g., collagen). Fibrous connective tissue is characterized by an extracellular matrix (ECM) with high collagen content. The collagen may be provided in the form of strands or fibers, which may be irregularly arranged or aligned. ECM of fibrous connective tissue may also include glycosaminoglycans.

As used herein, "excess fibrous connective tissue" refers to an amount of connective tissue at a given location (e.g., a given tissue or organ, or a portion of a given tissue or organ) that is greater than the amount of connective tissue present at the location in the absence of fibrosis, e.g., under normal, non-pathological conditions. As used herein, "excessive deposition of extracellular matrix components" refers to a level of deposition of one or more extracellular matrix components that is greater than the level of deposition in the absence of fibrosis, e.g., under normal, non-pathological conditions.

The cellular and molecular mechanisms of fibrosis are described in Wynn, j.pathol. (2008)214 (2): 199-: 1028-1040, which are herein incorporated by reference in their entirety. The primary cellular effector of fibrosis is myofibroblasts, which produce a collagen-rich extracellular matrix.

In response to tissue injury, damaged cells and leukocytes produce profibrotic factors, such as TGF β, IL-13, and PDGF, which activate fibroblasts to myofibroblasts expressing SMA, and recruit the myofibroblasts to the site of injury. Myofibroblasts produce a large amount of extracellular matrix and are important mediators that help wound contracture and closure. However, during persistent infection or chronic inflammation, myofibroblasts may be over-activated and recruited, over-producing extracellular matrix components, resulting in the formation of excess fibrous connective tissue.

In some embodiments, fibrosis may be caused by a pathological condition, e.g., a disorder, infection, or disease state that results in the production of a profibrotic factor, such as TGF β 1. In some embodiments, fibrosis may be caused by physical injury/stimulus, chemical injury/stimulus or environmental injury/stimulus. Physical damage/irritation may occur during surgery, such as iatrogenic causes. Chemical damage/irritation may include drug-induced fibrosis, for example, following chronic dosing with drugs such as bleomycin, cyclophosphamide, amiodarone, procainamide, penicillamine, gold and nitrofurantoin (Daba et al, Saudi Med J2004 Jun; 25 (6): 700-6). Environmental harm/irritation may include exposure to asbestos fibers or silica.

Fibrosis can occur in many tissues of the body. For example, fibrosis can occur in the lung, liver (e.g., cirrhosis), kidney, heart, blood vessels, eye, skin, pancreas, spleen, intestine (e.g., large or small intestine), brain, and bone marrow. Fibrosis may also occur in multiple organs simultaneously.

In embodiments herein, fibrosis may involve an organ of the gastrointestinal system, such as the liver, small intestine, large intestine or pancreas. In some embodiments, fibrosis may involve an organ of the respiratory system, such as the lung. In embodiments, fibrosis may involve an organ of the cardiovascular system, such as the heart or a blood vessel. In some embodiments, the fibrosis may involve the skin. In some embodiments, the fibrosis may involve an organ of the nervous system, such as the brain. In some embodiments, the fibrosis may involve an organ of the urinary system, such as the kidney. In some embodiments, fibrosis may involve an organ of the musculoskeletal system, e.g., muscle tissue.

In some preferred embodiments, the fibrosis is cardiac or myocardial fibrosis, liver fibrosis or kidney fibrosis. In some embodiments, the heart or myocardial fibrosis is associated with dysfunction of the myocardium or electrical properties of the heart or thickening of the walls or valves of the heart. In some embodiments, the fibrosis is an atrium and/or ventricle of the heart. Treatment or prevention of atrial or ventricular fibrosis may help to reduce the risk or onset of atrial fibrillation, ventricular fibrillation, or myocardial infarction.

In some preferred embodiments, liver fibrosis is associated with chronic liver disease or cirrhosis. In some preferred embodiments, the renal fibrosis is associated with chronic kidney disease.

Diseases/conditions characterized by fibrosis of the present invention include, but are not limited to: respiratory disorders such as pulmonary fibrosis, cystic fibrosis, idiopathic pulmonary fibrosis, progressive massive fibrosis, scleroderma, bronchiolitis obliterans, Hermansky-Pudlak syndrome, asbestosis, silicosis, chronic pulmonary hypertension, aids-related pulmonary hypertension, sarcoidosis, pulmonary tumor stroma, and asthma; chronic liver disease, Primary Biliary Cirrhosis (PBC), schistosome liver disease, cirrhosis; cardiovascular diseases such as hypertrophic cardiomyopathy, Dilated Cardiomyopathy (DCM), atrial fibrosis, atrial fibrillation, ventricular fibrosis, ventricular fibrillation, myocardial fibrosis, Brugada syndrome, myocarditis, endocardial fibrosis, myocardial infarction, fibrotic vascular diseases, hypertensive heart disease, Arrhythmogenic Right Ventricular Cardiomyopathy (ARVC), tubulointerstitial and glomerular fibrosis, atherosclerosis, varicose veins, cerebral infarction; nervous system diseases such as gliosis and Alzheimer's disease; muscular dystrophy, such as Duchenne Muscular Dystrophy (DMD) or Becker Muscular Dystrophy (BMD); gastrointestinal diseases such as crohn's disease, microscopic colitis and Primary Sclerosing Cholangitis (PSC); skin diseases such as scleroderma, nephrogenic systemic fibrosis and cutaneous keloids; fibrosis of joints; contracture of Dupuytren; mediastinal fibrosis; retroperitoneal fibrosis; myelofibrosis; pelonetz disease; adhesive capsulitis; kidney diseases (e.g., renal fibrosis, nephrotic syndrome, alport syndrome, HIV-associated nephropathy, polycystic kidney disease, fabry's disease, diabetic nephropathy, chronic glomerulonephritis, nephritis associated with systemic lupus erythematosus); progressive Systemic Sclerosis (PSS); chronic graft versus host disease; eye diseases/disorders and related processes, such as ocular disease by grave, preretinal fibrosis (e.g., Diabetic Retinopathy (DR)), glaucoma, subretinal fibrosis (e.g., associated with macular degeneration (e.g., wet age-related macular degeneration (AMD))), macular edema, drusen formation, post-operative fibrosis (e.g., capsular membrane after cataract surgery, or herpes after glaucoma trabeculectomy), conjunctival fibrosis, subconjunctival fibrosis; arthritis; pre-fibrotic tumors and fibrotic tumor diseases; fibrosis induced by chemical or environmental damage (e.g., cancer chemotherapy, pesticides, radiation/cancer radiotherapy).

It will be appreciated that many of the diseases/conditions listed above are interrelated. For example, ventricular fibrosis can occur following myocardial infarction and is associated with DCM, HCM and myocarditis.

In particular embodiments, the disease/disorder may be one of: pulmonary fibrosis, atrial fibrillation, ventricular fibrillation, Hypertrophic Cardiomyopathy (HCM), Dilated Cardiomyopathy (DCM), nonalcoholic steatohepatitis (NASH), cirrhosis, chronic kidney disease, scleroderma, systemic sclerosis, keloids, cystic fibrosis, crohn's disease, post-operative fibrosis or retinal fibrosis, for example associated with wet age-related macular degeneration (AMD).

Fibrosis may directly or indirectly lead to and/or increase susceptibility to disease/disorder development. For example, more than 80% of hepatocellular carcinomas (HCCs) develop in fibrotic or cirrhosis livers (Affo et al, 2016, Annu Rev Pathol.), suggesting an important role for liver fibrosis in the pre-malignant environment of the liver (PME).

Accordingly, the antibodies/fragments of the invention are useful in methods of treating and preventing diseases/disorders associated with fibrosis, and/or where fibrosis is a risk factor. In some embodiments, the disease/disorder associated with or at risk for fibrosis is cancer, for example liver cancer (e.g., hepatocellular carcinoma).

IL-11 is also involved in the pathology of other diseases/disorders, and thus the antibodies and fragments of the invention may also be used in methods of treating, preventing, and/or alleviating the symptoms of these diseases/disorders.

IL-11 is involved in the development and progression of various cancers. Studies have shown that IL-11 is important for promoting the development of chronic gastritis and related gastric, colon, hepatocellular, and breast cancers through over-activation of STAT3 (Ernst M, et al, JClin Invest. (2008); 118: 1727-. By STAT3, IL-11 promotes survival, proliferation, invasive angiogenesis and metastasis, the IL-11/GP130/JAK/STAT3 signaling axis may have a rate-limiting effect on the progression of gastrointestinal tumors, and elevated IL-11 expression has been associated with a prognosis in patients with poor breast cancer (Johnstone et al, cytokine and growth reviews (2015)26 (5): 489-498). IL-11 has also been shown to affect breast cancer stem cell kinetics and tumor heterogeneity (Johnstone et al, cytokine and growth reviews (2015)26 (5): 489-. More recently, IL-11 signaling has been associated with chemical resistance of lung adenocarcinoma; it was found that cancer-associated fibroblasts up-regulate IL-11 and confer chemoresistance to lung cancer cells by activating the IL-11/IL-11R/STAT3 anti-apoptotic signaling pathway (Tao et al, 2016, Sci Rep.6; 6: 38408). IL-11 signaling can promote the conversion of fibroblasts to myofibroblasts and production from the extracellular matrix of fibroblasts in premalignant environments (PME) and Tumor Microenvironments (TME).

In some embodiments, the antibodies/fragments of the invention are used in methods of treating/preventing cancer. In some embodiments, the cancer may be a cancer that directly or indirectly causes inflammation and/or fibrosis.

A cancer may be any unwanted cell proliferation (or any disease manifested by unwanted cell proliferation), or increase the risk or propensity of unwanted cell proliferation, a neoplasm or tumor, and a cancer may be benign or malignant, either primary or secondary (metastatic). A neoplasm or tumor can be any abnormal growth or proliferation of cells and can be located in any tissue.

In some embodiments, the antibodies/fragments of the invention are provided in a method for treating/preventing cancer, e.g., epithelial cell cancer, breast cancer, gastrointestinal cancer (e.g., esophageal cancer, gastric cancer, pancreatic cancer, liver cancer (e.g., HCC), gall bladder cancer, colorectal cancer, anal cancer, gastrointestinal carcinoid cancer) and lung cancer (e.g., non-small cell cancer (NSCLC) or Small Cell Lung Cancer (SCLC))). In some embodiments, the cancer is a cancer for which acute and/or chronic inflammation is a risk factor. In some embodiments, the cancer is a cancer for which a disease/disorder characterized by fibrosis (e.g., as described herein) is a risk factor.

In some embodiments, the cancer may be associated with increased IL-11, IL-11Ra and/or gp130 gene or protein expression. For example, a cancer cell may have increased expression of IL-11, IL-11Ra and/or gp130 compared to a comparable non-cancer cell, or may be associated with increased expression of IL-11, IL-11Ra and/or gp130 in other cells (e.g., non-cancer cells) compared to the expression level of a control cell in the absence of cancer (e.g., in a healthy control subject). In some embodiments, a cancer cell can be determined to have an increased level of signaling through the ERK and/or STAT3 pathway as compared to a comparable non-cancer cell.

In some embodiments, the cancer can be associated with mutations in IL-11, IL-11R α and/or gp 130. In some embodiments, such mutations may be associated with increased levels of gene or protein expression, or may be associated with increased levels of IL-11/IL-11R signaling relative to the levels of expression/signaling observed in the absence of the mutation.

IL-11 is also involved in diseases/disorders characterized by inflammation. Intra-articular injection of IL-11 has been shown to cause joint inflammation (Wong et al, cytokine (2005) 29: 72-76), and IL-11 has been shown to have pro-inflammatory properties at sites of IL-13 mediated tissue inflammation (Chen et al, J Immunol (2005) 174: 2305-2313). IL-11 expression was also observed to be significantly increased in chronic skin lesions of atopic dermatitis and is known to be involved in bronchitis (Toda et al, J Allergy Clin Immunol (2003) 111: 875-881). IL-11 mediated signaling is implicated in Inflammatory Bowel Disease (IBD) and asthma (Putoczki and Ernst, J Leuco Biol (2010)88(6) 1109-. IL-11 has also been identified as a risk factor for multiple sclerosis; IL-11 levels in cerebrospinal fluid of Clinically Isolated Syndrome (CIS) patients are elevated, serum IL-11 levels are elevated at relapse in relapsing remitting multiple sclerosis patients, and IL-11 may promote differentiation of CD4+ T cells to T cells as compared to control subjects_H17 phenotype-T_H17 cells are important cells in the pathogenesis of multiple sclerosis (Zhang et al, tumor target (2015)6 (32): 32297-32298).

In some embodiments, the antibodies/fragments of the invention are provided for use in a method of treating/preventing a disease/disorder characterized by inflammation. In some embodiments, the disease or disorder characterized by inflammation may be a disease/disorder that directly or indirectly leads to cancer and/or fibrosis. Diseases characterized by inflammation include allergic inflammation such as allergic asthma and bronchitis, atopic dermatitis, allergic rhinitis and ocular allergic diseases, multiple sclerosis, systemic lupus erythematosus, rheumatoid arthritis, chronic active hepatitis, type 1 diabetes, celiac disease, graves 'uveitis, pemphigus, psoriasis, crohn's disease, ulcerative colitis, inflammatory bowel disease, anemia and autoimmune thyroiditis.

In some embodiments, the antibodies/fragments of the invention are provided for use in methods of treating/preventing diseases/disorders associated with infection, particularly where the infection directly or indirectly results in fibrosis, cancer or inflammation. The disease associated with infection may be a disease caused or exacerbated by infection with the relevant infectious agent, or may be a disease in which infection with the relevant infectious agent is a risk factor.

The infection may be any infection or infectious disease, such as a bacterial, viral, fungal or parasitic infection. In particular embodiments, the disease/disorder may be associated with a viral infection. In some embodiments, it may be particularly desirable to treat chronic/persistent infections, for example, associated with inflammation, cancer, and/or fibrosis.

The infection may be chronic, persistent, latent or slow, and may be the result of a bacterial, viral, fungal or parasitic infection. Thus, treatment may be provided to patients suffering from bacterial, viral or fungal infections. Examples of bacterial infections include helicobacter pylori infection and mycobacterium tuberculosis infection. Examples of viral infections include EBV, HPV, HIV, hepatitis B or hepatitis C infections.

Treatment may include ameliorating, treating, or preventing a disease/disorder by inhibiting the biological activity of IL-11 or a complex comprising IL-11. These methods may comprise administering the antibodies/fragments/compositions of the invention to bind to and inhibit the biological activity of IL-11 or IL-11-containing complexes. Herein, inhibition of the biological activity of IL-11 or IL-11-containing complexes may be referred to as "neutralization".

The method of treatment may optionally include co-administration of a biological adjuvant (e.g., an interleukin, a cytokine, Bacillus calmette-Guerin (Bacillus comete-Guerin), monophosphoryl lipid a, etc.) in combination with conventional therapies for treating cancer, such as with agents for treating cancer (e.g., chemotherapy), radiation, or surgical treatment. Medical treatment methods may also involve in vivo, ex vivo and adoptive immunotherapy, including those using autologous and/or heterologous cells or immortalized cell lines.

Treatment may be aimed at preventing diseases/disorders associated with hyperactive/elevated IL-11 mediated signaling. Thus, the antibodies, antigen-binding fragments, and polypeptides can be used to formulate pharmaceutical compositions or medicaments, and subjects can be treated prophylactically to prevent the development of a disease state. This may occur prior to the onset of symptoms of the disease state, and/or may be administered to a subject considered to have a higher risk for the disease or disorder.

Administration of the antibody, antigen-binding fragment or polypeptide is preferably in a "therapeutically effective amount", which is sufficient to show benefit to the individual. The actual amount administered, the rate of administration and the time course will depend on the nature and severity of the disease being treated. The prescription of treatment, e.g. decisions regarding dosage etc., is under the responsibility of general practitioners and other medical doctors, and generally takes into account the condition to be treated, the condition of the individual patient, the site of labour, the method of administration and other factors known to practitioners. Examples of the above techniques and protocols can be found in Remington pharmacy, 20 th edition, 2000, pub.

Formulating pharmaceutically useful compositions and medicaments

The antibodies and antigen-binding fragments of the present invention may be formulated into pharmaceutical compositions or medicaments for clinical use and may contain pharmaceutically acceptable carriers, diluents, excipients or adjuvants.

The composition can be formulated for topical, parenteral, systemic, intracavitary, intravenous, intraarterial, intramuscular, intrathecal, intraocular, intraconjunctival, intratumoral, subcutaneous, oral, or transdermal routes of administration, which can include injection or infusion. Suitable formulations may comprise the antibody/fragment in sterile or isotonic medium. The medicaments and pharmaceutical compositions may be formulated as fluids, including in the form of gels. The fluid formulation may be formulated for administration to a selected region of the human or animal body by injection or by catheter.

According to the present invention there is also provided a process for the preparation of a pharmaceutically useful composition, which process may comprise one or more steps selected from: isolating an antibody or antigen-binding fragment as described herein; and/or mixing an isolated antibody or antigen-binding fragment as described herein with a pharmaceutically acceptable carrier, adjuvant, excipient, or diluent.

For example, another aspect of the invention relates to a method of formulating or producing a medicament or pharmaceutical composition for use in a method of medical treatment, the method comprising formulating the pharmaceutical composition or medicament by mixing an antibody or antigen-binding fragment described herein with a pharmaceutically acceptable carrier, adjuvant, excipient or diluent.

Detection method

The antibodies or antigen binding fragments described herein can be used in methods involving the binding of an antibody or antigen binding fragment to IL-11. Such methods may involve detecting a binding complex of an antibody or antigen-binding fragment and IL-11. Thus, in one embodiment, a method is provided that includes contacting a sample containing or suspected of containing IL-11 with an antibody or antigen-binding fragment as described herein and detecting the formation of a complex of the antibody or antigen-binding fragment and IL-11.

Suitable formats of methods are well known in the art and include immunoassays, such as sandwich assays, e.g., ELISA. The method may comprise labelling the antibody/antigen-binding fragment or IL-11 or both with a detectable label, such as a fluorescent, luminescent or radioisotope label. IL-11 expression can be measured by Immunohistochemistry (IHC), e.g., by biopsy of tissue samples. In some embodiments, the label may be selected from: radionucleotides, positron emitting radionuclides (e.g. for Positron Emission Tomography (PET)), MRI contrast agents or fluorescent labels.

In vitro or in vivo analysis of processes mediated by IL-11 may involve analysis by Positron Emission Tomography (PET), Magnetic Resonance Imaging (MRI) or fluorescence imaging, for example by detection of suitably labelled species.

Such a method may provide the basis for a method for diagnosing a disease or disorder requiring the detection and/or quantification of IL-11 or a complex comprising IL-11. These methods can be performed in vitro on a subject sample, or after processing of a subject sample. Once the sample is collected, the subject is not required to perform an in vitro diagnostic method, and thus the method may be a method that is not performed on the human or animal body.

Such methods may involve determining the amount of IL-11 or IL-11-containing complex present in a sample from the subject. The method may further comprise comparing the determined amount to a standard or reference value as part of the process of reaching the diagnosis. Other diagnostic tests may be used with those described herein to enhance the accuracy of the diagnosis or prognosis or to confirm the results obtained by using the tests described herein.

The level of IL-11 or IL-11-containing complex present in a sample from a subject can indicate that the subject can respond to treatment with an anti-IL-11 antibody/fragment, e.g., an anti-IL-11 antibody/fragment or composition of the invention, and the presence of high levels of IL-11 or IL-11-containing complex in the sample can be used to select subjects for treatment with an anti-IL-11 antibody/fragment or composition described herein. Accordingly, the antibodies of the invention can be used to select subjects for treatment with anti-IL-11 therapy.

Detection in a sample of a complex containing IL-11 or IL-11 can be used to diagnose an infectious disease, autoimmune disease, or cancer in a subject, to diagnose a susceptibility to an infectious disease, autoimmune disease, or cancer condition, or to provide a prognosis (prognosis) of an infectious disease, autoimmune disease, or cancer condition. The diagnosis or prognosis may relate to an existing (previously diagnosed) infectious, inflammatory or autoimmune disease/disorder or cancer condition.

Samples can be taken from any tissue or body fluid. The sample may comprise or may be derived from: a quantity of blood; a quantity of serum from the blood of the individual that may include a fluid portion of the blood obtained after removal of fibrin clots and blood cells; a tissue sample or biopsy; hydrothorax; cerebrospinal fluid (CSF); or a cell isolated from the individual. In some embodiments, the sample can be obtained or derived from a tissue or group of tissues affected by the disease/disorder (e.g., a tissue or group of tissues exhibiting symptoms of the disease or involved in the pathogenesis of the disease/disorder).

The method of the invention may preferably be carried out in vitro. The term "in vitro" is intended to include experiments in which cells are cultured, while the term "in vivo" is intended to include experiments and/or treatments of whole multicellular organisms.

Combination therapy

The antibodies, antigen-binding fragments, and compositions of the invention can be administered alone or in combination with other therapies. The administration of such combinations may be simultaneous or sequential depending on the disease/disorder to be treated. Other treatments to administer the antibodies/fragments or compositions may be directed to treating or preventing a disease/disorder. In some embodiments, the administration of the antibody/fragment or other treatment of the composition may be directed to the treatment or prevention of, for example, infection, inflammation, and/or cancer.

Simultaneous administration refers to administration of the antibody, antigen-binding fragment or polypeptide and the therapeutic agent together, e.g., as a pharmaceutical composition containing both agents (combined preparation), or immediately after each other, and optionally by the same route of administration, e.g., to the same artery, vein or other blood vessel.

Sequential administration refers to administration of one of the antibody, antigen-binding fragment or polypeptide or therapeutic agent after a given time interval by administering the other agent alone. Although this may be the case in some embodiments, it is not required that both agents be administered by the same route. The time interval may be any time interval.

In some embodiments, treatment with an antibody, antigen-binding fragment, or composition of the invention may be accompanied by an agent (e.g., an antibiotic, antiviral, antifungal, or antiparasitic agent) for treating or preventing infection. In some embodiments, treatment with an antibody, antigen-binding fragment, or composition of the invention may be accompanied by an agent (e.g., a non-steroidal anti-inflammatory drug (NSAID)) for treating or preventing inflammation. In some embodiments, treatment with an antibody, antigen-binding fragment, or composition of the invention can be accompanied by radiotherapy (i.e., treatment with ionizing radiation, such as X-rays or gamma rays) and/or an agent used to treat or prevent cancer (e.g., a chemotherapeutic agent). In some embodiments, the antibodies, antigen-binding fragments, or compositions of the invention may be administered as part of a combination therapy of immunotherapy.

Treatment may include administration of more than one drug. The drugs may be administered alone or in combination with other therapies, either simultaneously or sequentially depending on the condition to be treated.

Route of administration

The antibodies, antigen-binding fragments, medicaments and pharmaceutical compositions of aspects of the invention may be formulated for administration by a variety of routes including, but not limited to, parenteral, intravenous, intraarterial, intraocular, intraconjunctival, intramuscular, subcutaneous, intradermal, intratumoral injection or infusion, and oral administration. Antibodies, antigen-binding fragments, polypeptides and other therapeutic agents may be formulated in fluid or solid form. The fluid formulation may be formulated for administration to a selected region of the human or animal body by injection or infusion.

Reagent kit

In some aspects of the invention, a kit is provided. In some embodiments, the kit may have at least one container with a predetermined amount of antibody, fragment or composition. The kit may provide the antibodies/fragments in the form of a medicament or pharmaceutical composition, and may be provided with instructions for administration to a subject to treat a particular disease/disorder. The antibody, fragment or composition may be formulated so as to be suitable for injection or infusion into a tumor or blood.

In some embodiments, the kit may further comprise at least one container having a predetermined amount of another therapeutic agent (e.g., an anti-infective agent or a chemotherapeutic agent). In such embodiments, the kit may further comprise a second drug or pharmaceutical composition such that the two drugs or pharmaceutical compositions may be administered simultaneously or separately such that they provide a combined treatment for a particular disease or disorder. The therapeutic agent may also be formulated so as to be suitable for injection or infusion into the tumor or blood.

Test subject

The subject to be treated may be any animal or human. The subject is preferably a mammal, more preferably a human. The subject may be a non-human mammal, but more preferably is a human. The subject may be male or female. The subject may be a patient. The subject may have been diagnosed with a disease or disorder in need of treatment, or be suspected of having such a disease or disorder.

In some embodiments, the subject may be at risk of developing/contracting a disease or disorder.

Protein expression

Molecular biological techniques suitable for producing the proteins (e.g., antibodies/fragments) of the invention in cells are well known in the art, e.g., Sambrook et al, molecular cloning: a laboratory manual, new york: those set forth in cold spring harbor press, 1989.

The polypeptide may be expressed from a nucleotide sequence. The nucleotide sequence may be comprised in a vector present in the cell or may be incorporated into the genome of the cell.

As used herein, a "vector" is an oligonucleotide molecule (DNA or RNA) that is used as a vector to transfer exogenous genetic material into a cell. The vector may be an expression vector for expressing genetic material in a cell. Such vectors may include a promoter sequence operably linked to a nucleotide sequence encoding the gene sequence to be expressed. The vector may also include a stop codon and an expression enhancer. Any suitable vector, promoter, enhancer and stop codon known in the art may be used to express the polypeptide from the vectors of the invention. Suitable vectors include plasmids, binary vectors, viral vectors and artificial chromosomes (e.g., yeast artificial chromosomes).

In the present specification, the term "operably linked" may include situations where a selected nucleotide sequence and a regulatory nucleotide sequence (e.g., a promoter and/or enhancer) are covalently linked in a manner such that expression of the nucleotide sequence is affected or controlled by the regulatory sequence (thereby forming an expression cassette). Thus, a regulatory sequence is operably linked to a selected nucleotide sequence if it is capable of affecting transcription of the nucleotide sequence. The resulting transcript may then be translated into the desired protein or polypeptide, where appropriate.

Any cell suitable for expressing a polypeptide can be used to produce a polypeptide of the invention. The cell may be a prokaryote or a eukaryote. Suitable prokaryotic cells include E.coli. Examples of eukaryotic cells include yeast cells, plant cells, insect cells, or mammalian cells (e.g., Chinese Hamster Ovary (CHO) cells). In some cases, the cell is not a prokaryotic cell, as some prokaryotic cells do not allow the same post-translational modifications as eukaryotic organisms. Furthermore, there may be very high expression levels in eukaryotes, and proteins can be more easily purified from eukaryotes using appropriate tags. Specific plasmids which enhance secretion of the protein into the culture medium may also be used.

Methods of producing a polypeptide of interest can include culturing or fermenting the modified cell to express the polypeptide. The cultivation or fermentation may be carried out in a bioreactor with a suitable supply of nutrients, air/oxygen and/or growth factors. Secreted proteins can be collected by partitioning the culture medium/fermentation broth from the cells, extracting the protein content, and isolating individual proteins to isolate the secreted polypeptide. Culture, fermentation and isolation techniques are well known to those skilled in the art.

The bioreactor comprises one or more vessels in which cells can be cultured. The culture in the bioreactor can be carried out continuously, with a constant inflow of reactants and a continuous flow of cultured cells from the reactor. Alternatively, the cultivation may be carried out batchwise. The bioreactor monitors and controls environmental conditions such as pH, oxygen, inflow and outflow rates, and agitation within the vessel to provide optimal conditions for the cultured cells.

After culturing the cells expressing the polypeptide of interest, the polypeptide is preferably isolated. Any suitable method for isolating polypeptides from cell cultures known in the art may be used. To isolate a polypeptide of interest from a culture, it may be necessary to first separate the cultured cells from the medium containing the polypeptide of interest. If the polypeptide of interest is secreted from the cells, the cells can be separated from the medium containing the secreted polypeptide by centrifugation. If the polypeptide of interest is aggregated within the cells, the cells must be disrupted prior to centrifugation, for example using sonication, rapid freeze-thawing or osmotic lysis. Centrifugation will produce a pellet containing the cultured cells or cell debris of the cultured cells, as well as a supernatant containing the culture medium and the polypeptide of interest.

It may then be desirable to isolate the polypeptide of interest, which may contain other proteinaceous and non-proteinaceous components, from the supernatant or the culture medium. A common method for isolating the polypeptide fraction from the supernatant or the culture medium is by precipitation. Polypeptides/proteins of different solubilities are precipitated in different concentrations of a precipitating agent, such as ammonium sulfate. For example, water soluble proteins are extracted at low concentrations of precipitant. Thus, by adding increasing concentrations of precipitating agent, proteins of different solubilities can be distinguished. Dialysis can then be used to remove ammonium sulfate from the isolated protein.

Other methods for distinguishing between different polypeptides/proteins are known in the art, such as ion exchange chromatography and size chromatography. These may be used as an alternative to precipitation or may be carried out after precipitation.

Once the polypeptide of interest is isolated from the culture, it may be desirable to concentrate the protein. Many methods of concentrating a protein of interest are known in the art, such as ultrafiltration or lyophilization.

Sequence identity

The alignment used to determine percent amino acid or nucleotide sequence identity can be achieved in a variety of ways known to those skilled in the art, for example, using publicly available computer software, such as ClustalW 1.82.T-coffee or megalign (dnastar) software. When such software is used, default parameters, such as gap penalties and extension penalties, are preferably used. The default parameters for ClustalW 1.82 are: protein gap opening penalty of 10.0, protein gap extension penalty of 0.2, protein matrix of Gonnet, protein/DNA ENDGAP of-1, protein/DNA GAPDIST of 4.

The invention includes combinations of the described aspects and preferred features unless such combinations are clearly not allowed or explicitly avoided.

The section headings used herein are for organizational purposes only and are not to be construed as limiting the subject matter described.

Aspects and embodiments of the present invention will now be described by way of example with reference to the accompanying drawings. Other aspects and embodiments will be apparent to those skilled in the art. All documents mentioned herein are incorporated herein by reference.

Throughout this specification, including the claims which follow, unless the context requires otherwise, the word "comprise", and variations such as "comprises" and "comprising", will be understood to imply the inclusion of a stated integer or step or group of integers or steps. But does not exclude any other integer or step or group of integers or steps.

It must be noted that, as used in the specification and the appended claims, the singular forms "a," "an," and "the" include plural referents unless the context clearly dictates otherwise. Ranges can be expressed herein as from "about" one particular value, and/or to "about" another particular value. When such a range is expressed, another embodiment includes from the one particular value and/or to the other particular value. Similarly, when values are expressed as approximations, by use of the antecedent "about," it will be understood that the particular value forms another embodiment.

Brief Description of Drawings

Embodiments and experiments illustrating the principles of the present invention will now be discussed with reference to the accompanying drawings, in which:

FIG. 1 shows read depth maps of whole transcriptome sequencing of human atrial fibroblasts from 160 individuals with and without TGF β 1 stimulation.

Figure 2 is a graph showing expression of endothelial tissue, cardiomyocytes, and fibroblast marker genes determined by RNA-seq of source tissue (human atrial tissue sample, n-8) and primary unstimulated fibroblast cultures. (A) PECAM1, (B) MYH6(C) TNNT2, (D) COL1A2, and (E) ACTA 2.

FIG. 3 is a graph showing the upregulation of IL-11 expression in fibroblasts in response to TGF β 1 stimulation. (A and B) graphs showing fold-change in gene expression in fibrosis; IL-11 is the most upregulated gene in response to TGF β 1 therapy. (C) In response to TGF β 1 stimulation, fibroblasts secrete IL-11. (D) Comparison of IL-11 Gene expression in tissues of healthy individuals and atrial fibroblasts with or without stimulation by TGF β 1. (E) Correspondence of fold change in IL-11 expression determined by RNA-seq versus qPCR.

FIG. 4 is a graph showing the induction of IL-11 secretion in primary fibroblasts by various profibrotic cytokines determined by ELISA. (A) TGF beta 1, ET-1, AngII, PDGF, OSM and IL-13 induce IL-11 secretion, IL-11 also induces IL-11 expression in a positive feedback loop. (B) Shows ELISA only from cells secreted natural IL-11, and not detected for IL-11 stimulation conditions of recombinant IL-11 diagram. (C) And (D) with recombinant IL-11 stimulation of cells, measurement of IL-11RNA and at the specified time points by ELISA measurement of the cell culture supernatant in the native IL-11 protein level.

FIG. 5 is a graph and image showing the production of myofibroblasts and the production of ECM and cytokine expression from atrial fibroblasts in response to stimulation with TGF β 1 or IL-11. (A) Myofibroblasts and ECM produced by primary atrial fibroblasts following stimulation with TGF β 1 or IL-11, as measured by fluorescence microscopy after staining for α -SMA, collagen or periostin. (B) Collagen content of cell culture supernatants determined by sirius red staining. Secretion of the fibrosis markers (C) IL-6, (D) TIMP1 and (E) MMP2 measured by ELISA. (F) Mouse fibroblasts were activated by stimulation with human or mouse recombinant IL-11. P <0.05, P <0.01, P <0.001, P <0.0001[ mean ± SD, Dunnett ].

FIG. 6 is a graph showing the fibrosis promoting effect of IL-11. (A) Mouse fibroblasts from tissues of different origins can be activated by IL-11 and show increased production of ECM. [ mean. + -. SD, Dunnett ]. Injection of mice with recombinant IL-11 or AngII resulted in (B) an increase in organ weight [ mean. + -. SEM ], and (C) an increase in collagen content (as determined by HPA assay). P <0.05, P <0.01, P <0.001, P <0.0001[ mean ± SD, Dunnett ].

FIG. 7. graph and image show that IL-11 requires the profibrotic action of TGF β 1 on fibroblasts. (A) Myofibroblast production and ECM production from primary atrial fibroblasts, with or without TGF β 1 stimulation, and the presence/absence of neutralizing anti-IL-11 antibodies or isotype control IgG, as measured by fluorescence microscopy after staining for (a) α -SMA, (B) EdU or (C) periodontin. (D to F) the secretion of the fibrosis markers (D) IL-6, (E) TIMP1 and (F) MMP2 were analyzed by ELISA. Fluorescence was normalized to control in the absence of stimulation. [ mean ± SD, Dunnett ]. P <0.05,. P <0.01,. P <0.001 or. P < 0.0001.

FIG. 8 is a graph and image showing the effect of IL-11 neutralization on TGF-beta 1-triggered collagen production. Cardiac fibroblasts stimulated or not with TGF β 1 produce collagen in the presence/absence of neutralizing anti-IL-11 antibody or isotype control IgG as determined by (a) Operetta assay or (B) sirius red staining. [ mean ± SD, Dunnett ]. P <0.05,. P <0.01,. P <0.001 or. P < 0.0001.

FIG. 9 is a graph showing the ability of various IL-11 and IL-11R α antagonists to inhibit fibrosis. Human atrial fibroblasts were treated with neutralizing antibodies to IL-11, neutralizing antibodies to IL-11R α, decoy IL-11 receptor molecules that bind IL-11, siRNAs that down-regulate IL-11 expression, or siRNAs that down-regulate IL-11RA expression, and the effect on TGF β 1-driven profibrotic response in vitro fibroblasts was analyzed. [ mean ± SD, Dunnett ]. P <0.05,. P <0.01,. P <0.001 or. P < 0.0001.

FIG. 10 is a bar graph showing the response of fibroblasts from IL-11-RA knockout mice to profibrotic therapy. Fibroblasts derived from IL-11RA WT (+/+), heterozygous (+/-), and homozygous null (-/-) mice were incubated with TGF β 1, IL-11 or AngII (5ng/ml) for 24 hours. (A) The percentage of myofibroblasts determined by analysis of alpha SMA content, (B) the percentage of proliferating cells determined by EdU staining, (C) collagen content determined by detection of periostin and (D) ECM produced [ mean ± SD ].

FIG. 11 is a graph showing the effect of IL-11 neutralization on fibrosis in response to various profibrotic stimuli. The production of (A) collagen and (B) myofibroblast production were determined by assaying for alpha SMA expression in the presence/absence of various profibrotic factors, in the presence/absence of neutralizing anti-IL-11 antibodies or pan-anti-TGF-beta antibodies. [ mean ± SD, Dunnett ]. P <0.05,. P <0.01,. P <0.001 or. P < 0.0001.

FIG. 12 is a bar graph showing the expression of fibrosis markers in the atria and heart of WT and IL-11RA (-/-) animals after treatment with AngII. (A) Collagen content measured by hydroxyproline assay. (B) Collagen (Col1a2) expression. (C) α SMA (ACTA2) expression. (D) Fibronectin (Fn1) expression.

FIG. 13 is a schematic representation of experimental procedures for analyzing fibrosis in (A) lung, (B) skin and (C) eye of IL-11 RA-/-mice compared to IL-11RA +/+ mice.

FIG. 14 is a scatter plot showing fold change in gene expression. (A) Fold change in gene expression in fibroblasts following stimulation with TGF β 1, IL-11 or TGF β 1 and IL-11. (B) Fold change in gene expression in fibroblasts obtained from IL-11RA +/+ and IL-11 RA-/-mice after stimulation with TGF β 1.

FIG. 15 is the light chain variable region sequence of human anti-IL-11 antibody clones. CDRs are underlined and shown separately.

FIG. 16 is the heavy chain variable region sequence of human anti-IL-11 antibody clones. CDRs are underlined and shown separately.

FIG. 17 shows a table of light chain CDR sequences of human anti-IL-11 antibody clones.

FIG. 18 shows a table of heavy chain CDR sequences of human anti-IL-11 antibody clones.

FIG. 19 is a table showing light chain CDR sequences of human anti-IL-11 antibody clones and consensus sequences for (A) LC-CDR1, (B) LC-CDR2, and (C) LC-CDR 3.

FIG. 20 shows a table of heavy chain CDR sequences of human anti-IL-11 antibody clones and consensus sequences of (A) HC-CDR1, (B) HC-CDR2 and (C) HC-CDR 3.

FIG. 21. Table summarizing panning strategies for identifying human anti-human IL-11 antibodies capable of binding to human IL-11 and mouse IL-11.

FIG. 22 is a scatter plot showing the intensity of binding signals to human IL-11 and mouse IL-11 as determined by ELISA assay for 86 human anti-IL-11 antibody candidates.

FIG. 23 is a table summarizing 56 human anti-human IL-11 antibody clones.

FIG. 24 is a bar graph showing the inhibition of IL-11 mediated signaling by human anti-IL-11 antibodies in human atrial fibroblasts in vitro, after stimulation with TGF β 1, as determined by fold change in the percentage of α SMA positive cells compared to control (unstimulated) fibroblasts. (A) Bar graph showing fold change in the proportion of α SMA positive cells relative to unstimulated cells (═ 1). (B) Bar graph showing the percentage of α SMA positive cells (activated fibroblasts).

FIG. 25 is a bar graph showing the inhibition of IL-11-mediated signaling by human anti-IL-11 antibodies in vitro in (A) mouse atrial fibroblasts and (B) mouse dermal fibroblasts following stimulation with TGF β 1 in the presence of human anti-IL-11 antibodies, as determined by fold change in the percentage of α SMA-positive cells compared to control (unstimulated) fibroblasts.

FIG. 26. Bar graph shows the inhibition of in vitro ultra IL-11 mediated IL-11 trans signaling by human anti-IL-11 antibodies in human atrial fibroblasts following stimulation with ultra IL-11 in the presence of human anti-IL-11 antibodies, as determined by fold change in the percentage of α SMA positive cells compared to control (unstimulated) fibroblasts.

FIG. 27 is a table summarizing fold change data for the 56 human anti-IL-11 antibodies of FIGS. 24-26. Antibody candidates numbered 1 through 56 correspond to the clone names shown in fig. 23. The industry standard was monoclonal mouse anti-IL-11 IgG 2A; clone # 22626; item number MAB 218; r & D system, MN, usa.

FIG. 28 shows a graph of human anti-IL-11 antibody binding to human IL-11 as determined by ELISA assays. (A) ELISAs of clones YU45-A3, YU45-A10, YU45-D11, YU45-E11, YU45-D12 and YU33-A2 (IgG). (B) ELISAs of clones YU45-G1, YU45-B2, YU45-A5, YU45-E3, YU45-F8 and YU33-H3 (IgG). (C) ELISAs of clones YU45-G8, YU45-F9, YU45-H10, YU45-F2, YU45-H3 and YU33-E3 (IgG). (D) ELISAs of clones YU45-A8, YU45-B5, YU45-D9, YU45-G7, YU45-B6 and YU 45-F9. (E) ELISAs of clones YU45-F5, YU46-B5, YU45-C1, YU46-A8, YU46-B6 and YU 45-F9. (F) ELISAs of clones YU46-E3, YU46-G8, YU46-D3, YU45-B6, YU45-C1 and YU 45-F9.

FIG. 29 summarizes the EC of human anti-IL-11 antibody binding to IL-11 as determined by ELISA assay₅₀Table of values.

FIG. 30 is a schematic representation of an antibody light chain replacement process.

FIG. 31. Table summarizing 16 mouse anti-human IL-11 antibody clones.

FIG. 32. bar graph shows the inhibition of IL-11 mediated signaling in vitro by mouse anti-IL-11 antibodies in human atrial fibroblasts in the presence of mouse anti-IL-11 antibodies after stimulation with TGF β 1, as determined by fold change in the percentage of α SMA positive cells compared to control (unstimulated) fibroblasts.

FIG. 33. Bar graph shows the inhibition of IL-11-mediated signaling in vitro by mouse anti-IL-11 antibodies in mouse atrial fibroblasts in the presence of mouse anti-IL-11 antibodies after stimulation with TGF β 1, as determined by fold change in the percentage of α SMA positive cells compared to control (unstimulated) fibroblasts.

FIG. 34 bar graph shows inhibition of in vitro ultra IL-11 mediated IL-11 trans signaling in human atrial fibroblasts by mouse anti-IL-11 antibody in the presence of mouse anti-IL-11 antibody following stimulation with ultra IL-11, as determined by fold change in the amount of MMP2 in cell culture supernatants compared to control (unstimulated) fibroblasts.

FIG. 35 is a table summarizing fold change data for the 16 mouse anti-IL-11 antibodies of FIGS. 32-34. Antibody candidates numbered 1 to 16 correspond to the clone names shown in fig. 31. The industry standard was monoclonal mouse anti-IL-11 IgG 2A; clone # 22626; item number MAB 218; r & D system, MN, usa.

FIG. 36. Table and bar graphs (A) summarizing experimental results as determined by iQue analysis showing binding of mouse anti-IL-11 antibody to human IL-11. (B) Bar graph showing binding strength against positive control anti-FLAG antibody (100%); the numbers correspond to the clones shown in fig. 35.

FIG. 37 is a graph showing the effect of IL-11RA knockdown on folate-induced renal fibrosis, as measured by collagen content in renal tissue.

FIG. 38 is a photograph showing the effect of IL-11RA knockout on wound healing and fibrosis in the eye after trabeculectomy (filter surgery). (A) 7 days after filtration surgeryEye sections of IL-11RA +/+ (WT) and IL-11RA-/- (KO) animals. (B) Maturation of collagen fibers assessed by picric acid-sirius red polarized light technique: (Et al, 1984, Acta Morphol Hung 32, 47-55); more fibrosis was observed in WT mice than KO mice.

FIG. 39 shows that IL-11 is required for the profibrosis of TGF β 1 in liver fibroblasts. Activation and proliferation of primary human liver fibroblasts were determined by analyzing the ratio of (a) α -SMA positive cells, and (B) EdU positive cells, (C) collagen positive cells and (D) periostin positive cells, in the presence/absence of neutralizing anti-IL-11 antibody or isotype control IgG, with or without stimulation with TGF β 1, compared to unstimulated cells (baseline). [ mean ± SD, Dunnett ]. P <0.05,. P <0.01,. P <0.001 or. P < 0.0001.

FIG. 40 bar graph shows that IL-11 is required for the profibrotic action of TGF β 1 in skin fibroblasts. Activation of mouse skin fibroblasts was determined by analyzing the percentage of α -SMA positive cells (activated fibroblasts) in the presence/absence of neutralizing anti-IL-11 antibodies with or without TGF β 1 stimulation.

FIG. 41 is a bar graph showing migration of lung fibroblasts with and without IL-11 signaling. Lung fibroblasts from IL-11RA +/+ (WT) and IL-11RA-/- (KO) animals were analyzed for migration in an in vitro scratch test in the absence of stimulation or in the presence of TGF β 1 or IL-11.

FIG. 42 is a graph showing fibroblast activation in response to hyperil-11. Cells were stimulated with indicated amounts (in ng/ml) of either super IL-11 or recombinant IL-11 and fibroblast activation was determined by analyzing the percentage of α -SMA positive cells. (A) And (B) gives the results of two different experiments.

FIG. 43 is a graph showing that hyperil-11 induces IL-11 secretion in primary fibroblasts. Cells were stimulated with super IL-11 and IL-11RNA and native IL-11 protein levels were determined by ELISA in cell culture supernatants at the indicated time points.

FIG. 44 is the light chain variable region sequence of human anti-IL-11 antibody clones after light chain replacement. CDRs are underlined and shown separately.

FIG. 45 heavy chain variable region sequence of human anti-IL-11 antibody clones after light chain replacement. CDRs are underlined and shown separately.

FIG. 46 shows a table of light chain CDR sequences of human anti-IL-11 antibody clones following light chain replacement.

FIG. 47 shows a table of heavy chain CDR sequences of human anti-IL-11 antibody clones after light chain replacement.

FIG. 48 shows a table of light chain CDR sequences and consensus sequences for human anti-IL-11 antibody clones following light chain replacement of (48A) LC-CDR1, (48B) LC-CDR2 and (48C) LC-CDR 3.

FIG. 49 shows a table of heavy chain CDR sequences and consensus sequences for human anti-IL-11 antibody clones after light chain replacement of (49A) HC-CDR1, (49B) HC-CDR2 and (49C) HC-CDR 3.

FIG. 50 amino acid sequence of single chain variable antibody fragment (ScFv) of human anti-IL-11 antibody clone after light chain substitution.

FIG. 51 nucleotide sequence encoding scFv of a human anti-IL-11 antibody clone following light chain substitution.

FIG. 52. Table summarizing panning strategies for identifying human anti-human IL-11 antibodies capable of binding to human IL-11 and mouse IL-11 following light chain replacement.

FIG. 53. dot-plot shows binding signals to human IL-11 and mouse IL-11, human anti-IL-11 antibody with light chain replacement as determined by ELISA assay. 66 antibodies (black circles) were identified that showed cross-reactive binding to human IL-11 and mouse IL-11. Only antibodies that show binding to mouse IL-11 are indicated by gray circles.

FIG. 54 bar graph (FIG. 54A) and table (FIG. 54B) show binding signals of human IL-11 and mouse IL-11 determined by ELISA for 64 unique light chain-substituted human anti-IL-11 antibodies.

FIG. 55. histogram shows the EC50 values of ng/ml for binding of indicated light chain substituted anti-IL-11 antibodies to human IL-11, as determined by ELISA.

FIG. 56 bar graph shows the effect of anti-IL-11 antibodies on the secretion of MMP2 by human atrial fibroblasts in response to TGF β 1. Fig. 56A and 56B show the results of two independent experiments. Cells were cultured for 24 hours in the presence of the indicated light chain-substituted anti-IL-11 antibody, or in the presence of a human IgG1 isotype control, in the presence of TGF β 1(5 ng/ml). Secretion of basal MMP2 by cells in culture was determined by culturing in the absence of TGF β 1 in the presence of a human IgG1 isotype control. The horizontal lines show basal MMP2 secretion of atrial cardiac fibroblasts cultured for 24 hours in the presence of human IgG1 isotype control antibody in the absence of TGF β 1 (NEG); atrial human fibroblasts cultured for 24 hours in the presence of 5ng/ml TGF β and human IgG1 isotype control antibody (POS) secrete MMP 2.

FIG. 57 is a table summarizing the results of FIGS. 55 and 56, which relate to functional characterization of anti-IL-11 antibody clones showing light chain substitutions. N.d. not determined.

Fig. 58A and 58B. Images and graphs show the results of histological analysis of mouse kidney sections subjected to different treatments in a mouse model of renal fibrosis. By reaction on a carrier (0.3M NaHCO)₃) Intraabdominal (IP) injection of folic acid (FA, 180mg/kg) in mice induces renal fibrosis; control mice were given vehicle alone. Mice were administered isotype control IgG2(20mg/kg, 3X weekly, intraperitoneally), anti-IL-11 antibody (20mg/kg, 3X weekly, intraperitoneally) starting on day 1 of the experimental period after folate injury. Animals were sacrificed 28 days after folate-induced kidney injury and fibrosis was analyzed histologically using masson trichrome staining. (58A) Image of masson trichrome stained kidney section. Fibrous regions containing collagen appear darker than healthy regions that appear lighter. (58B) A graph showing a semi-quantitative analysis of collagen area, expressed as a percentage (%) of total kidney area (graph). Compared to FA + IgG, ANOVA<0.001。

Figure 59 is a graph showing urinary albumin/creatine ratios in mice subjected to different treatments in a renal fibrosis mouse model. By reaction on a carrier (0.3M NaHCO)₃) Intraabdominal (IP) injection of folic acid (FA, 180mg/kg) in mice induces renal fibrosis; control mice were given vehicle alone. FA treated mice were administered isotype control throughout the experiment starting on day 1 after folate injuryIgG2(20mg/kg, 3X weekly, intraperitoneally) or anti-IL 11 antibody (20mg/kg, 3X weekly, intraperitoneally). Mice were placed in metabolic cages and urine creatinine and albumin were measured using a commercial assay (Abcam) according to the manufacturer's instructions. Compared to FA + IgG, ANOVA<0.001。

Figure 60 is a graph showing total collagen in mouse kidney tissue subjected to different treatments in a renal fibrosis mouse model. By reaction on a carrier (0.3M NaHCO)₃) Intraabdominal (IP) injection of folic acid (FA, 180mg/kg) in mice induces renal fibrosis; control mice were given vehicle alone. Starting on the first day of the experiment, mice in the treated groups were given different doses of isotype control IgG2(20mg/kg, 3 x weekly) or neutralizing anti-IL 11 antibody: 20mg/kg × 3/week; 10mg/kg × 3/week; 10mg/kg × 2/week; 5mg/kg × 3/week; 5mg/kg × 2/week; 1mg/kg × 2/week), all intraperitoneal injections. Animals were sacrificed 28 days post injection and renal fibrosis (micrograms/g (μ g/g)) was analyzed by hydroxyproline assay according to the manufacturer's protocol using the QuickZyme total collagen detection kit (QuickZyme Biosciences). Compared to FA + IgG, ANOVA:, P<0.01；***，P<0.001。

Figures 61A and 61b images and graphs show histological analysis results of mouse kidney sections subjected to different treatments in an acute kidney injury mouse model. (61A) Mice were treated by sham surgery or ureteral occlusion of the ureter. Mice received IgG, anti-IL-11 antibody (day-1, 1,3,5, 20mg/kg) and injured kidneys (UUO IgG, IL-11) or uninjured kidneys on contralateral (Con) (Con IgG, IL-11) were harvested on day 7 post-surgery. (61B) Semi-quantitative assessment of tubular lesions was determined by histological analysis of tubular atrophy or tubular dilatation blinded to experimental conditions (tubular lesion score: 0, none; 1, min; 2, mild; 3, moderate; 4, severe). P <0.05 compared to UUO IgG, ANOVA.

FIG. 62 is a graph showing ELISA Western blot results for IL-11 of human liver samples. Liver samples obtained from patients undergoing liver surgery were used for western blot analysis. Blots of GAPDH were used as loading controls. Samples from Normal Human Liver (NHL) had low levels of IL-11 protein, whereas samples from fibrotic liver disease, including Alcoholic Liver Disease (ALD), Primary Sclerosing Cholangitis (PSC), Primary Biliary Cirrhosis (PBC) or non-alcoholic steatohepatitis (NASH), had higher levels of IL-11.

FIG. 63 bar graph shows the results of ELISA analysis of IL-11 secretion from human PCLS subjected to different treatments.

Fig. 64A and 64B. The images and graphs show the results of an analysis of mouse liver tissue subjected to different treatments in a non-alcoholic steatohepatitis mouse model. Diabetic mice (db/db; leptin receptor deficient) were maintained on normal diet (left, circled) or NASH induced (methionine/choline deficiency (MCD)) diet for 8 weeks. In one group of animals, neutralizing anti-IL 11 antibody (20mg/kg, 3X/week, i.p.) was administered during the last 3 weeks of the 8-week NASH diet. Liver samples were photographed (64A) and evaluated for collagen content per mg of liver tissue (64B); each symbol represents an individual animal. P values are shown on a graph, ANOVA.

Fig. 65A and 65B. The bar graph and image show the results of an analysis of ocular fibrosis for mice subjected to different treatments in a mouse model of retinal fibrosis. Mice (10 per group) were subjected to laser-induced retinal damage (4 burns per retina) and given 0.5 μ g anti-IL-11 antibody or IgG control antibody within the eyes on days 1,7,14 and 21. Eyes were harvested for histological analysis on day 28. The area of fibrosis in the burn area was determined by masson trichrome staining. (65A) The bar graph shows quantification of fibrotic regions in control (IgG) or anti-IL 11(IL11) treated mice. (65B) Representative images showing staining of fibrotic regions in control antibody-treated eyes (IGG, top panel) or anti-IL 11-treated eyes (IL11, bottom panel).

Fig. 66A to 66C. Schematic, image and bar graphs relating to mouse skin fibrosis analysis with different treatments in a mouse model of skin fibrosis. (66A) Schematic of experimental procedures for different treatment groups. Groups 1 and 2 were treated with Bleomycin (BLM) and anti-IL-11 antibody (group 1) or IgG control antibody (group 2). Group 3 injected vehicle (PBS) only, and no fibrosis occurred. (66B) The images show a masson trichrome staining of skin sections at equal distances from the injection site. The dermis thickness is indicated by the black bar. (66C) Bar graphs showing the results of the dermal thickness analysis (treatment groups were blinded). The mean dermal thickness was determined from the bottom of the epithelial layer to the top of the dermal white adipose tissue layer for 40 fields of each sample. Each dot represents an animal. P values were calculated using unpaired two-tailed t-test.

FIG. 67 is an image showing the results of histological analysis of mouse cardiac fibrosis subjected to different treatments in a mouse model of cardiac fibrosis. Mice (C57B16, male, 8-12 weeks old) were subject to fibrosis-induced transverse aortic stenosis (TAC) or sham surgery. TAC treated animals received either control antibody (20mg/kg, 3X/week, i.p.) or neutralizing anti-IL-11 antibody (20mg/kg, 3 times/week, i.p.). Hearts were harvested two weeks later and the degree of fibrosis was assessed using masson trichrome staining.

FIG. 68 heavy chain variable region sequences of mouse anti-IL-11 antibody clones. CDRs are underlined and shown separately.

FIG. 69 sequence of the variable region of the light chain of the mouse anti-IL-11 antibody clone. CDRs are underlined and shown separately.

FIG. 70 shows a table of heavy chain CDR sequences of mouse anti-IL-11 antibody clones.

FIG. 71 shows a table of light chain CDR sequences of mouse anti-IL-11 antibody clones.

FIG. 72 is a table showing the heavy chain CDR sequences and consensus sequences for mouse anti-IL-11 antibody clones of (72A) HC-CDR1, (72B) HC-CDR2 and (72C) HC-CDR 3.

FIG. 73. Table of light chain CDR sequences and consensus sequences for mouse anti-IL-11 antibody clones showing (73A) LC-CDR1, (73B) LC-CDR2 and (73C) LC-CDR 3.

FIG. 74 nucleotide sequences encoding the heavy and light chains of mouse anti-IL-11 antibody clones.

Examples

In the following examples, the inventors identified the role of IL-11/IL-11R signaling in fibrosis in various tissues and described the production of anti-human IL-11 antibodies, as well as functional characterization of the antibodies in vitro and in vivo.

Example 1: role of IL-11 in fibrosis

1.1 IL-11 upregulation in fibrosis

To understand the molecular processes underlying the transformation of fibroblasts into activated myofibroblasts, atrial tissue was obtained from more than 200 patients undergoing cardiac bypass surgery at the national heart center of singapore. Cells were cultured in vitro in the lower channels (channel <4) and stimulated or not with TGF β 1 for 24 hours. We then performed high throughput RNA sequencing (RNA-seq) analysis of unstimulated fibroblasts and cells stimulated with prototype profibrotic stimulation TGF β 1, analyzing 160 individuals; the average read depth was 70M reads per sample (100 bp for paired ends; FIG. 1).

To ensure the purity of atrial fibroblast cultures, we analyzed the expression of atrial-derived endothelial cells, cardiomyocytes and fibroblast type marker genes in the RNA-seq dataset (Hsu et al, 2012 circulatory cardiovasc Genetics 5, 327-.

The results are shown in fig. 2A to 2E, and confirm the purity of the atrial fibroblast culture.

Gene expression was assessed by RNA-seq of source tissue (human atrial tissue sample, n ═ 8) and primary unstimulated fibroblast cultures. No/very low expression of the endothelial cell marker PECAM1 (fig. 2A) and the cardiomyocyte markers MYH6 (fig. 2B) and TNNT2 (fig. 2C) was detected in fibroblast culture samples. Markers for fibroblast cells COL1a2 (fig. 2D) and ACTA2 (fig. 2E) were highly expressed compared to the original tissue.

Next, the RNA-seq data was analyzed to identify genes whose expression increased or decreased following stimulation with TGF β 1, and this information was integrated with the large RNA-seq dataset in 35+ human tissue provided by the GTEx project (GTEx alliance, 2015 science 348, 648-660). This enables the identification of gene expression markers specific for fibroblast-myofibroblast transition.

The results are shown in fig. 3A to 3E. Of the 10000 genes expressed in fibroblasts, IL-11 is the most strongly upregulated gene in response to TGF β 1 stimulation, and the average of 160 individuals is upregulated more than 10-fold (fig. 3B).

ELISA analysis of cell culture supernatants from fibroblasts stimulated by TGF β 1 confirmed the upregulation of IL-11 expression (FIG. 3C). This response was observed to be highly specific for activated fibroblasts compared to the expression level of IL-11 in other tissues of healthy individuals (fig. 3D). Various fold-changes in IL-11RNA expression were also confirmed by qPCR analysis (FIG. 3E).

Next, fibroblasts were cultured in vitro and stimulated with several other known profibrotic factors: ET-1, ANGII, PDGF, OSM and IL-13, and human recombinant IL-11. To analyze the upregulation of IL-11 production in response to IL-11 stimulation, it was demonstrated that ELISA was only able to detect native IL-11 secreted from cells, and not recombinant IL-11 for stimulation (FIG. 4B).

The results are shown in FIG. 4A. Each factor was found to significantly induce the secretion of IL-11 by fibroblasts. IL-11 was shown to function in the autocrine loop of fibroblasts, which can lead to up-regulation of IL-11 protein by up to 100-fold after 72 hours (FIG. 4D).

Interestingly, this autocrine loop of IL-11 is similar to the autocrine production of IL-6. IL-6 is from the same cytokine family and also signals through the gp130 receptor (Garbers and Scheller, 2013 Biol Chem 394,1145-1161), which is proposed to ensure the continued survival and growth of lung and breast cancer cells (Grvennikov and Karin, 2008 cancer cells 13, 7-9).

No increase in IL-11RNA levels was detected in response to IL-11 stimulation (FIG. 4D). Unlike TGF-beta 1, TGF-beta 1 increases IL-11 expression at both the RNA and protein levels, and thus IL-11 appears to only upregulate IL-11 expression at the post-transcriptional level.

1.2 IL-11 has a profibrotic effect in the fibrosis of cardiac tissue

To investigate whether the autocrine production of IL-11 was profibrotic or anti-fibrotic, fibroblasts were cultured in vitro with recombinant IL-11 and the ratio of myofibroblasts (α SMA-positive cells) and extracellular matrix production was analyzed.

Expression of α SMA, collagen and periostin was monitored in an automated, high-throughput manner using an Operetta high-content imaging system. Meanwhile, the secretion of fibrosis marker proteins such as MMP2, TIMP1 and IL-6 was analyzed by ELISA assay, and the level of collagen was confirmed by calorimetric sirius red analysis of cell culture supernatant.

Briefly, atrial fibroblasts from 3 individuals were incubated in 2 wells for 24 hours each without stimulation, with TGF β 1(5ng/ml) or with IL-11(5 ng/ml). After incubation, cells were stained to analyze alpha-SMA content to estimate the ratio of myofibroblasts, collagen and periostin to estimate the ECM produced. Fluorescence was measured at 7 fields per well. The collagen content of the supernatants of 2 wells of each individual was also assessed by sirius red staining. Signals were normalized to the control group in the absence of stimulation. Secretion of the fibrosis markers IL-6, TIMP1 and MMP2 were analyzed by ELISA.

The results are shown in fig. 5A to 5F. TGF β 1 activates fibroblasts and increases ECM production (fig. 5A). Unexpectedly, in contrast to the anti-fibrotic effects described by IL-11 in cardiac tissue in the scientific literature, recombinant IL-11 caused an increase in the proportion of myofibroblasts in fibroblast cultures and also promoted the production of the extracellular matrix proteins collagen and periostin to the same extent as TGF β 1 (FIG. 5A). Both IL-11 and TGF β 1 cytokines also significantly increased secretion of the profibrotic markers IL-6, TIMP1 and MMP2 (fig. 5B to 5E), and reached similar levels.

The inventors hypothesized that, at present, IL-11 was found to be profibrotic in cardiac tissue, and the contradiction between the antifibrotic effects described in the literature may be related to the use of human IL-11 in rodents in previous studies (Obana et al, 2010, 2012; Stangou et al, 2011; Trepicchio and Dorner, 1998).

To investigate this hypothesis, serial dilutions of human and mouse IL-11 were performed and activation of human atrial fibroblasts was monitored (fig. 5F). No fibroblast activation was observed in mouse cells at low concentrations of human IL-11, suggesting that previous insights into IL-11 function may be due in part to the observation of IL-11 non-specificity.

1.3 IL-11 has a profibrotic effect in fibrosis in various tissues

To test whether the profibrotic effect of IL-11 is specific for atrial fibroblasts, human fibroblasts from several different tissues (heart, lung, skin, kidney and liver) were cultured in vitro, stimulated with human IL-11, and analyzed for fibroblast activation and ECM production as described above. Increased fibroblast activation and ECM production was observed compared to unstimulated cultures in fibroblasts from each tissue analyzed.

1.3.1 hepatic fibrosis

To test whether IL-11 signaling is important in liver fibrosis, human primary hepatic fibroblasts (Cell Biologics, Cat #: H-6019) were cultured in low channel in wells of 96-well plates, either unstimulated, or incubated with TGF β 1(5ng/ml, 24H), IL-11(5ng/ml, 24H) stimulated or with TGF β 1(5ng/ml) and neutralizing IL-11 antibody (2 μ g/ml) or TGF β 1(5ng/ml) and isotype control antibody. Fibroblast activation (α SMA positive cells), cell proliferation (EdU positive cells) and ECM production (periodidin and Collagen) were analyzed using the Operetta platform.

Experimental results of primary human liver fibroblasts are shown in fig. 39A to 39D. IL-11 was found to activate liver fibroblasts, and IL-11 signaling was found to be essential for the profibrosis of TGF β 1 in liver fibroblasts. The activation and proliferation of fibroblasts is inhibited by neutralizing anti-IL-11 antibodies.

1.3.2 skin fibrosis

To test whether IL-11 signaling is important in skin fibrosis, primary mouse skin fibroblasts were cultured in wells of 96-well plates at low throughput, unstimulated, or stimulated with TGF β 1(5ng/ml, 24h) or incubated with TGF β 1(5ng/ml) and neutralizing IL-11 antibody (2 μ g/ml) for 24 hours. Fibroblast activation (α SMA positive cells) was then analyzed using the Operetta platform.

The results are shown in fig. 40. TGF-beta 1-mediated activation of skin fibroblasts is inhibited by neutralizing anti-IL-11 antibodies.

1.3.3 multiple organ fibrosis

Next, mouse recombinant IL-11 (100. mu.g/kg, 3 days/week, 28 days) was injected into mice to test whether IL-11 could drive systemic tissue fibrosis in vivo.

The results are shown in fig. 6. IL-11 also increased cardiac weight compared to injection of AngII, a cytokine that caused elevated blood pressure and cardiac hypertrophy, but also increased body mass index kidney, lung and liver weights (FIG. 6B). Assessment of collagen content in these questions by hydroxyproline assay revealed upregulation of collagen production in these tissues, suggesting that fibrosis is a possible cause of organ weight gain (fig. 6C). Expression of fibrosis marker genes ACTA2(═ α SMA), Col1a1, Col3a1, Fn1, Mmp2 and Timp1 was also examined by qPCR analysis of RNA isolated from heart, kidney, lung and liver tissues of these animals.

Example 2: therapeutic potential of IL-11/IL-11R antagonism

2.1 inhibition of fibrotic response Using neutralizing antagonists of IL-11/IL-11R

Next, it was investigated whether the profibrotic action of TGF-. beta.1 on fibroblasts requires an autocrine loop for IL-11 secretion.

IL-11 was inhibited using a commercially available neutralizing antibody (monoclonal mouse IgG 2A; clone # 22626; cat # MAB 218; R & D system, MN, USA). Fibroblasts were treated with TGF β 1 in the presence or absence of antibodies and markers of fibroblast activation, proportion of proliferating cells and ECM production and fibrotic response were determined.

Briefly, atrial fibroblasts from 3 individuals were incubated with TGF-beta 1(5ng/ml) or TGF-beta 1 for 24 hours in the presence of neutralizing anti-IL-11 antibody or isotype control antibody. After incubation, cells were stained for α SMA to determine the proportion of myofibroblasts, the proportion of proliferating cells was determined by analyzing the cells for EdU incorporation, and periostin was measured to determine ECM production. Fluorescence was measured for 14 fields in 2 wells per individual using an Operetta platform. Secretion of the fibrosis markers IL-6, TIMP1 and MMP2 were also analyzed by ELISA. Fluorescence was normalized to the control group in the absence of stimulation.

The results are shown in fig. 7A to 7F. IL-11 inhibition was found to ameliorate TGF-1-induced fibrosis, and IL-11 was shown to be essential for the profibrosis of TGF-1. Inhibition of IL-11 was found to "rescue" the TGF-beta 1 phenotype at the protein level.

Collagen production was also analyzed. Cardiac fibroblasts from 3 individuals were incubated with TGF-beta 1(5ng/ml) or TGF-beta 1 and neutralizing IL-11 antibody for 24 hours. After incubation, cells were stained for collagen using the Operetta assay and fluorescence quantified as described above. Secreted collagen levels in cell culture supernatants were assessed by sirius red staining.

The results are shown in FIGS. 8A and 8B and demonstrate inhibition of anti-fibrotic effects of IL-11 using neutralizing antibodies.

Next, several other IL-11/IL-11R antagonists were analyzed for their ability to inhibit fibrosis in vitro using the atrial fibroblast, TGF β 1-induced myofibroblast switch assay described herein above.

Briefly, human atrial fibroblasts were cultured in vitro and stimulated with TGF β 1(5ng/ml) for 24 hours or unstimulated, in the presence or absence of: (i) neutralizing an anti-IL-11 antibody, (ii) IL-11RA-gp130 fusion protein (iii) neutralizing an anti-IL-11 RA antibody, (iv) treatment with siRNA against IL-11 or (v) treatment with siRNA against IL-11 RA. The proportion of activated fibroblasts (myofibroblasts) was analyzed by assessing alpha SMA content as described above.

The results are shown in fig. 9. It was found that each antagonist of IL-11/IL-11R signaling was capable of abrogating TGF-beta 1-mediated profibrotic responses.

Example 3: in vivo confirmation of profibrosis of IL-11/IL-11R signalling

3.1 in vitro Studies Using cells from IL-11RA knockout mice

All mice were bred and housed in the same room, with food and water ad libitum. Mice lacking functional alleles of IL-11R α (IL-11RA1 KO mice) are on a C57Bl/6 genetic background. The mice were 9-11 weeks old, and there was no significant difference in animal body weight.

To further demonstrate the anti-fibrotic effect of inhibiting IL-11 signaling, primary fibroblasts obtained from animals with IL-11RA +/+ (i.e., wild-type), IL-11RA +/(i.e., heterozygous knockout), and IL-11 RA-/(i.e., homozygous knockout) of TGF β 1, IL-11, or AngII were generated from IL-11RA knockout mice and incubated with primary fibroblast instrumentation. Fibroblast cells and ECM production were analyzed for activation and proliferation.

Fibroblasts derived from IL-11RA +/+, IL-11RA +/-and IL-11 RA-/-mice were incubated with TGF β 1, IL-11 or AngII (5ng/ml) for 24 hours. After incubation, cells were stained for alpha SMA content to estimate the proportion of myofibroblasts, EdU was used to identify the proportion of proliferating cells, and collagen and periostin were used to estimate ECM production. Fluorescence was measured using an Operetta platform.

The results are shown in fig. 10A to 10D. IL-11 RA-/-mice were found to be non-responsive to profibrotic stimulation. These results indicate that IL-11 signaling is also necessary for AngII-induced fibrosis.

Next, it was investigated whether other profibrotic cytokines do so as well.

Briefly, fibroblasts were cultured in vitro in the presence/absence of various different profibrotic factors (ANG2, ET-1 or PDGF), in the presence/absence of neutralizing anti-IL-11 antibodies or pan-anti-TGF β antibodies. After 24 hours, collagen production by the cells was determined by analysis using the Operetta system as described above, and myofibroblast production was determined by alpha SMA expression analysis as described above.

The results are shown in FIGS. 11A and 11B. IL-11 was found to be essential for a variety of profibrotic stimuli downstream fibrosis and was therefore identified as a central mediator of fibrosis induced by a variety of different profibrotic factors.

In further experiments, the role of IL-11 signaling in pulmonary fibrosis was investigated using an in vitro scratch test of lung fibroblast migration. In response to a profibrotic stimulus, fibroblasts are activated and migrate within the fibrotic niche in the body. Cell mobility is a measure of cell-cell and cell-matrix interactions and a model of wound healing in vivo (Liang et al, 2007; Nat Protoc.2 (2): 329-33).

Fibroblasts from lung tissue of Wild Type (WT) and homozygous IL-11RA (-/-) knockout mice were grown on plastic surfaces at low flux until they formed a uniform cell monolayer. Scratches were then created in the cell layer and cell migration near the scratch was monitored in the absence of stimulation or in the presence of TGF β 1 or IL-11. Images captured at the images at two time points of 24 hours immediately after creation of the scratch were used to determine the area of cell coverage and compare the migration rate between WT and KO fibroblasts. Cell migration (scratched area covered by cells after 24 hours) was normalized to the migration rate of WT cells without stimulation.

The results are shown in FIG. 41. The lung fibroblasts from WT mice were shown to migrate more rapidly in the presence of TGF β 1 and IL-11, indicating the profibrotic action of both cytokines in lung fibroblasts. Cells lacking IL-11 signaling from KO mice migrated more slowly than WT cells. They also do not migrate faster in the presence of TGF β 1. Scratch experiments showed that lung fibroblasts lacking IL-11 signaling had reduced cell mobility in the presence of TGF β 1 or IL-11 and at baseline. Thus, inhibition of IL-11 signaling is anti-fibrotic in the lung.

3.2 cardiac fibrosis

The efficacy of IL-11 inhibition in the treatment of fibrotic diseases was studied in vivo. Treatment of mouse models of cardiac fibrosis inducing fibrosis with AngII was used to investigate whether IL-11 RA-/-mice were protected from cardiac fibrosis.

Briefly, the pump was implanted and Wild Type (WT) IL-11RA (+/+) and knock-out (KO) IL-11RA (-/-) mice were treated with AngII (2 mg/kg/day) for 28 days. At the end of the experiment, collagen content was assessed in the atria of mice using a calorimetric hydroxyproline-based assay kit, and the RNA expression levels of markers or fibrotic Col1a2, alpha SMA (ACTA2) and fibronectin (Fn1) were analyzed by qPCR.

The results are shown in fig. 12A to 12D. IL-11 RA-/-mice were found to be protected from the profibrotic action of AngII.

3.3 renal fibrosis

By reaction on a carrier (0.3M NaHCO)₃) Folic acid (180mg/kg) is injected in the middle abdomen, and IL-11RA (+) is Wild Type (WT)Establishing mouse models for renal fibrosis in both the/+) and knock-out (KO) IL-11RA (-/-) mice; control mice were given vehicle alone.

Kidneys were removed 28 days post injection, weighed and fixed in formalin in 10% neutral buffer for masson trichrome and sirius staining or flash frozen for collagen determination, RNA and protein studies.

Total RNA was extracted from flash-frozen kidneys using Trizol reagent (Invitrogen) and the Qiagen tissue lyzer method, followed by RNeasy column (Qiagen) purification. cDNA was prepared using the iScriptTM cDNA synthesis kit, where each reaction contained 1. mu.g of total RNA, according to the manufacturer's instructions. The gene expression analysis of the RT-PCR was performed quantitatively on triplicate samples using either TaqMan (applied biosystems) or Rapid SYBR Green (Qiagen) techniques for 40 cycles using StepOneNus (TM) (applied biosystems). Expression data were normalized to GAPDH mRNA expression levels, and we calculated fold changes using the 2- Δ Δ Ct method. The rapidly frozen kidneys were subjected to acid hydrolysis by heating in 6M HCl at a concentration of 50mg/ml (95 ℃, 20 hours). The amount of total collagen in the hydrolysate was determined by hydroxyproline-based colorimetric assay using the Quickzyme whole collagen detection kit (Quickzyme Biosciences) according to the manufacturer's instructions.

The analysis results are shown in fig. 37. Folate-induced renal fibrosis was shown to be dependent on IL-11 mediated signaling. A significant increase in collagen content in renal tissue was observed in IL-11RA +/+ mice, indicating renal fibrosis. No significant increase in collagen content was observed in IL-11 RA-/-mice. Animals lacking IL-11 signaling had significantly reduced collagen deposition in the kidney following toxic injury compared to wild-type animals.

3.4 pulmonary fibrosis

In a further in vivo model using IL-11 RA-/-knockout mice, IL-11 was identified as a key mediator of fibrosis in the lung, skin and eye. Schematic diagrams of the experiments are shown in fig. 13A to 13C.

To analyze pulmonary fibrosis, IL-11 RA-/-and IL-11RA +/+ mice were treated on day 0 by intratracheal administration of bleomycin to establish a fibrotic response in the lungs (pulmonary fibrosis). Pulmonary fibrosis developed for 21 days, at which time animals were sacrificed and analyzed for differences in fibrotic markers between animals with and without IL-11 signaling. IL-11 RA-/-mice have a reduced fibrotic response in lung tissue as compared to IL-11RA +/+ mice, as evidenced by a reduced expression of a fibrotic marker.

3.5 skin fibrosis

To analyze fibrosis of the skin, IL-11 RA-/-and IL-11RA +/+ mice were treated on day 0 by subcutaneous administration of bleomycin to establish a fibrotic response in the skin. Skin fibrosis developed for 28 days, at which time animals were sacrificed and analyzed for differences in fibrosis markers between animals with and without IL-11 signaling. IL-11 RA-/-mice have reduced fibrotic response in skin tissue as compared to IL-11RA +/+ mice, as evidenced by reduced expression of fibrotic markers.

3.6 ocular fibrosis

To analyze fibrosis in the eye, IL-11 RA-/-and IL-11RA +/+ mice received trabeculectomy (filtration surgery) on day 0 to elicit a wound healing response in the eye. This mouse model of glaucoma filtration surgery has proven to be an effective model for assessing wound healing responses in the eye (Khaw et al, 2001, Curr Opin Ophthalmol 12, 143-.

Briefly, the conjunctiva is dissected to expose the underlying sclera, after which an incision is made through the sclera into the anterior chamber of the eye using a 30-gauge needle. The resulting fistula allows the aqueous humor to enter the conjunctiva and below. The incised conjunctiva is then secured and closed over the limbus by a 10-0(0.2 metric) loeve black monofilament nylon scleral suture. The fujix ointment was instilled at the end of the surgery. Surgery was performed under anesthesia by intraperitoneal injection of 0.1ml of a ketamine/xylazine mixture, and topical application of one drop of 1% lidocaine per eye. The ointment named Fuzi was added slowly after the operation to prevent infection. Surgery was performed with surgical scissors and forceps sterilized with 70% propanol and a sterile needle.

The fluid accumulated under the sutured conjunctiva was observed as a conjunctival vesicle. Mice were euthanized for analysis on day 7 post-surgery. For qualitative immunohistological analysis, eyes from mice will be harvested by enucleation and then sectioned. Evaluation of collagen fiber maturation Using picric acid-sirius Red polarized light technique (Et al, 1984, Acta Morphol Hung 32, 47-55); orange red indicates mature collagen and yellow/green indicates newly formed immature collagen.

The results of the experiment are shown in FIGS. 38A and 38B. IL-11R-/-mice were found to have reduced fibrotic response in ocular tissues compared to IL-11RA +/+ mice.

3.7 other tissues

The effect of IL-11RA knockdown on fibrosis was also analyzed in mouse models for fibrosis of other tissues (e.g. liver, intestine), and also in models associated with multi-organ (i.e. systemic) fibrosis. Fibrosis responses were measured and compared between IL-11 RA-/-mice and IL-11RA +/+ mice. IL-11 RA-/-mice have reduced fibrotic response compared to IL-11RA +/+ mice, as evidenced by reduced expression of fibrotic markers.

Example 4: analysis of the potential molecular mechanisms of IL-11-mediated fibrosis induction

The canonical mode of action of IL-11 is thought to be through STAT 3-mediated transcription, and also through activation of ERK to regulate RNA expression (Zhu et al, 2015PLoS ONE 10, e 0126296).

STAT3 activation was observed following stimulation with IL-11. However, when fibroblasts were incubated with TGF β 1, only activation of the classical SMAD pathway and ERK pathway was observed, and no activation of STAT3 was observed, even though IL-11 was secreted in response to TGF β 1. Only ERK activation is common to both TGF β 1 and IL-11 signaling.

The cross-effect between TGF β 1 and IL-6 signaling has been previously described in which TGF β 1 blocks IL-6 activation of STAT3 (Walia et al, 2003 FASEB J.17, 2130-. In view of the close relationship between IL-6 and IL-11, similar cross effects of IL-11 mediated signaling can be observed.

The present inventors investigated, through RNA-seq analysis, whether modulation of RNA abundance is a potential mechanism for increased expression of fibrosis marker proteins in response to IL-11, suggesting that STAT3 is a potential signaling pathway for IL-11 mediated profibrosis. Fibroblasts were incubated for 24 hours without stimulation or in the presence of TGF beta 1, IL-11 or TGF beta 1 and IL-11.

The results are shown in fig. 14A. TGF β 1 induces the expression of collagen, ACTA2(α SMA) and other fibrotic markers at the RNA level. However, IL-11 does not regulate the expression of these genes, but rather a diverse set of genes.

Gene ontology analysis indicated that profibrosis in fibroblasts was driven by IL-11 regulated RNA expression. Both TGF-beta 1 and IL-11 regulate an almost completely different set of genes at the RNA level.

Although TGF-beta 1 increases IL-11 secretion, when both TGF-beta 1 and IL-11 are present, the target gene for IL-11 is not regulated. This suggests that TGF-beta 1 upregulates IL-11 and simultaneously blocks classical IL-11 driven regulation of RNA expression by STAT3, similar to the known interaction of TGF-beta 1 and IL-6 pathways (Walia et al, 2003 FASEB J.17, 2130-2132).

We also analyzed whether the TGF-beta 1-induced RNA expression differences were dependent on IL-11 signaling by analyzing changes in RNA expression in fibroblasts obtained from IL-11 RA-/-mice compared to IL-11RA +/+ mice. RNA expression regulated by TGF-beta 1 is still observed when IL-11RA knockout cells are stimulated with TGF-beta 1, and RNA levels of α SMA, collagen, etc., are still up-regulated in the absence of IL-11 signaling (in IL-11 RA-/-fibroblasts). When IL-11 profibrosis and IL-11 inhibition anti-fibrotic effects were studied in vitro, reduced expression of fibrotic markers was observed only at the protein level, not at the transcriptional level as determined by qPCR.

Activation of non-classical pathways (e.g., ERK signaling) is known to be critical for the profibrosis of TGF β 1 (Guo and Wang, 2008 Cell Res 19, 71-88). For all known pro-fibrotic cytokine signaling, the non-classical pathway may be important, and IL-11 is essential for fibrosis in the post-transcriptional regulator.

Example 5: human anti-human IL-11 antibodies

Fully human anti-human IL-11 antibodies were developed by phage display.

Recombinant human IL-11 (cat # Z03108-1) and recombinant murine IL-11 (cat # Z03052-1) were obtained from GenScript (NJ, USA). Recombinant human IL-11 is expressed in CHO cells, both as Fc-tagged and unlabeled. Marker-free murine IL-11 is expressed in HEK293 cells.

The IL-11 bioactivity of recombinant human IL-11 and murine IL-11 was confirmed by in vitro analysis using primary fibroblast cultures.

Recombinant biotinylated human IL-11 and murine IL-11 were also prepared by biotinylation of recombinant human IL-11 and murine IL-11 molecules according to standard methods.

Through the use of biotinylated and non-biotinylated recombinant human and murine IL-11 panning, using human natural library, through phage display identification capable of binding to human IL-11 and murine IL-11 antibody (i.e. cross-reactive antibodies), based on figure 21 in the summary of 16 different panning strategies.

Phage display identified 175 scFv binders as "first hits". Sequence analysis of the CDR sequences from these 175 scfvs identified 86 unique scfvs.

Soluble scFv were generated by recombinant expression in E.coli and analyzed for their ability to bind to human IL-11 and murine IL-11 by ELISA. Briefly, the corresponding antigen was coated in wells of an ELISA plate at 1: cell culture supernatants containing each scFv were added at 2 dilutions and binding was detected.

The results of ELISA analysis of binding human IL-11 and murine IL-11 are shown in FIG. 22. Analysis shows that:

8 scFVs could only bind to human IL-11;

6 scFv were only able to bind murine IL-11;

32 scFv only show weak binding to human/murine IL-11, with high signal-to-noise ratio, and;

40 scFv were cross-reactive to both human IL-11 and murine IL-11.

From these 86 scFV, 56 candidates were selected for further functional characterization. For further analysis, the scFV was cloned into scFV-Fc form in e.

The antibody clone names are shown in FIG. 23.

The amino acid sequence information of the antibodies is shown in figures 15 to 20.

The VH and VL sequences of the antibody were cloned into an expression vector to produce scFv-Fc (human IgG1) antibodies. The vectors are transiently expressed in mammalian cells cultured in serum-free media and isolated by protein a purification.

Example 6: functional characterization of human anti-human IL-11 antibodies

Analysis of the antibodies described in example 5 in an in vitro assay has the following capabilities:

(i) inhibit human IL-11-mediated signaling, (ii) inhibit mouse IL-11-mediated signaling, and (iii) inhibit IL-11 trans-signaling through IL-11 complexed with IL-11 RA. The affinity of the antibodies to human IL-11 was also analyzed by ELISA.

6.1 ability to inhibit human IL-11 mediated signalling

To investigate the ability to neutralize human IL-11 mediated signaling, cardiac atrial human fibroblasts were cultured in the presence of TGF β 1(5ng/ml) in the presence or absence of anti-IL-11 antibody in wells of 96-well plates for 24 hours. TGF β 1 promotes expression of IL-11, which in turn drives the conversion of resting fibroblasts into activated α SMA positive fibroblasts. It has been previously shown that neutralization of IL-11 can prevent TGF β 1-induced transformation to activated α SMA positive fibroblasts.

Expression of α SMA was analyzed in an automated high-throughput manner using an Operetta high-content imaging system.

In unstimulated cultures, 29.7% (═ 1) fibroblasts were α SMA positive activated fibroblasts at the end of the 24 hour culture period, while 52% (═ 1.81) fibroblasts were α SMA positive in cultures stimulated with TGF β 1 in the absence of anti-IL-11 antibodies.

anti-IL-11 antibody (2. mu.g/ml) was added to fibroblast cultures stimulated with TGF β 1 and at the end of the 24 hour incubation period the percentage of α SMA positive fibroblasts was determined. Percentages were normalized based on the percentage of α SMA positive fibroblasts observed in fibroblast cultures not stimulated with TGF β 1.

The experimental results are shown in fig. 24A, 24B and 27. It was demonstrated that 28 antibodies were able to neutralize human IL-11 mediated signaling.

Commercial monoclonal mouse anti-IL-11 antibodies (monoclonal mouse IgG 2A; clone # 22626; cat # MAB 218; R & D Systems, MN, USA) were also analyzed for their ability to inhibit human IL-11 signaling in the experiments. This antibody was found to be able to reduce the percentage of activated fibroblasts to 28.3% (-0.99).

Several clones neutralized human IL-11 signaling to a greater extent than commercially available mouse anti-IL-11 antibodies (industry standard): YU45-C11/A10(#6), YU45-G1(#11), YU45-E3(#16), YU45-F8(#18), YU45-F9(#21), YU45-H10(#22), YU45-F2(#24), YU45-H3(#25), YU45-G7(#33), YU45-B6(#36), YU45-C1(#42), YU46-B6(#47), YU46-E3(#50), YU46-G8(#54), and YU46-D3(# 56).

6.2 ability to inhibit IL-11 mediated signalling in mice

Following the same procedure as described in section 6.1 above, but using mouse atrial fibroblasts instead of human atrial fibroblasts, the ability of human antibodies to inhibit mouse IL-11 mediated signaling was also investigated.

After 24 hours of culture, approximately 31.8% (═ 1) unstimulated cells in the culture were activated fibroblasts. Stimulation with TGF β 1 resulted in a 2-fold increase in the percentage of activated fibroblasts compared to non-stimulated cultures (68.8% — 2.16).

The results of the experiment are shown in fig. 25 and 27. Antibodies were shown to neutralize signaling mediated by mouse IL-11. Monoclonal mouse IgG2A clone #22626, anti-IL-11 antibody to MAB218, was also analyzed for its ability to inhibit mouse IL-11 signaling. This antibody was found to be able to reduce the percentage of activated fibroblasts to 39.4% (═ 1.24).

Several clones neutralized IL-11 signaling in mouse atrial fibroblasts to a greater extent than commercially available mouse anti-IL-11 antibodies (industry standard): YU-B/YU-G/A (#3), YU-H/D (#9), YU-G (#11), YU-D/H/C/F/C/E/E/C/G/H/C/A/A (#14), YU-B (#15), YU-F (#18), YU-H (#22), YU-A (#23), YU-A/C (#27), YU-D/D (#31), YU-B (#36), YU-C (#42), YU-A (#45), YU-C (#48), YU-H (#52), YU-G (#54), and YU-D (# 56).

The ability of human antibodies to inhibit mouse IL-11-mediated signaling was also investigated using mouse skin fibroblasts.

The results of the experiment are shown in fig. 27. Antibodies were shown to neutralize signaling mediated by mouse IL-11.

Several clones neutralized IL-11 signaling in mouse skin fibroblasts to a greater extent than commercially available mouse anti-IL-11 antibodies (industry standard): YU45-B6(#36), YU45-C1(#42), and YU46-H8(# 52).

6.3 the ability of complexes of IL-11 with IL-11RA to inhibit IL-11 trans-signaling

Trans-signaling is considered to be a major aspect of IL-6 signaling, where a complex of IL-6 and soluble IL-6 Ra can activate gp 130-expressing cells lacking the IL-6 receptor (Hunter and Jones, 2015 Nature electronics 16, 448-457).

It has recently been suggested that the trans-signaling of the IL-11 and soluble IL-11RA complexes is also important for IL-11 biology (Lokau et al, Cell Reports (2016)14, 1761-1773). Using recombinant fusion proteins of IL-11 and IL-11R α (as described in Pflanz et al, Febs Lett (1999) 450: 117-122), anti-IL-11 antibodies were screened for inhibition of IL-11: the ability of the IL-11R α complex to mediate trans-signaling.

Importantly, it inhibits classical IL-11-mediated signaling and IL-11: antibodies to IL-11 trans-signaling of the IL-11R α complex are capable of inhibiting all known IL-11/IL-11R signaling patterns.

IL-11: IL-11R α fusion proteins (hereinafter referred to as superIL-11) are composed of the extracellular domain of IL-11 receptor α (IL-11R α) linked to IL-11.

It was found that hyperil-11 is a more potent human fibroblast activator than recombinant IL-11 protein. Briefly, in two separate experiments, human fibroblasts were cultured in the presence of different amounts of super IL-11(0.008ng/ml, 0.04ng/ml, 0.2ng/ml, 1ng/ml and 5ng/ml) without stimulation (baseline), or recombinant human IL-11 obtained from commercial sources, and fibroblast activation was analyzed by determining the percentage of α SMA positive cells as described herein. The results are shown in (FIGS. 42A and 42B). HyperIL-11 activates fibroblasts in a dose-dependent manner and is a more potent activator than IL-11.

L-11: IL-11R α fusion proteins were prepared as follows:

coding for IL-1: the DNA of the 1IL-11R α fusion protein (i.e., SEQ ID NO: 265) will be cloned into the pTT5 vector and in serum-free FreeStyle^TM293 expression Medium (Thermo Fisher Scientific) was transfected into 293-6E cells.

Cells were incubated on an orbital shaker (VWR Scientific) at 37 ℃ with 5% CO₂The lower part was kept in an Erlenmeyer flask (Corning Inc.).

Cell culture supernatants were collected for purification on day 6.

The cell culture supernatant is applied to an affinity purification column.

After washing and elution with the appropriate buffer, the eluted fractions are pooled and the buffer is changed to the final formulation buffer.

Analysis of purified IL-11 by SDS-PAGE, Western blot: IL-11R α fusion protein to confirm molecular weight and purity.

Encoding IL-11: DNA of IL-11R α fusion protein (SEQ ID NO: 265):

GAATTCCCGCCGCCACCATGGGCTGGTCCTGCATCATCCTGTTTCTGGTGGCCACAGCCACCGGCGTGCACTCTCCACAGGCTTGGGGACCTCCAGGCGTGCAGTATGGCCAGCCTGGCAGATCCGTGAAGCTGTGCTGTCCTGGCGTGACAGCTGGCGACCCTGTGTCCTGGTTCAGAGATGGCGAGCCCAAGCTGCTGCAGGGCCCAGATTCTGGACTGGGCCACGAACTGGTGCTGGCCCAGGCCGATTCTACCGACGAGGGCACCTACATCTGCCAGACCCTGGATGGCGCCCTGGGCGGAACAGTGACACTGCAGCTGGGCTACCCTCCCGCCAGACCTGTGGTGTCTTGTCAGGCCGCCGACTACGAGAACTTCAGCTGCACATGGTCCCCCAGCCAGATCAGCGGCCTGCCCACCAGATACCTGACCAGCTACCGGAAGAAAACCGTGCTGGGCGCCGACAGCCAGAGAAGAAGCCCTTCTACAGGCCCCTGGCCCTGCCCTCAGGATCCTCTGGGAGCTGCCAGATGTGTGGTGCACGGCGCCGAGTTCTGGTCCCAGTACCGGATCAACGTGACCGAAGTGAACCCCCTGGGCGCCTCCACAAGACTGCTGGATGTGTCCCTGCAGAGCATCCTGCGGCCCGATCCTCCACAGGGCCTGAGAGTGGAAAGCGTGCCCGGCTACCCCAGAAGGCTGAGAGCCAGCTGGACATACCCCGCCTCTTGGCCTTGCCAGCCCCACTTCCTGCTGAAGTTTCGGCTGCAGTACCGGCCAGCCCAGCACCCTGCTTGGAGCACAGTGGAACCTGCCGGCCTGGAAGAAGTGATCACAGACGCCGTGGCCGGACTGCCTCATGCTGTGCGGGTGTCCGCCAGAGACTTTCTGGATGCCGGCACCTGGTCTACCTGGTCCCCAGAAGCCTGGGGCACACCTTCTACTGGCGGACCTGCTGGACAGTCTGGCGGAGGCGGAGGAAGTGGCGGAGGATCAGGGGGAGGATCTGTGCCTGGACCTCCTCCAGGACCCCCTAGAGTGTCCCCAGATCCTAGGGCCGAGCTGGACTCTACCGTGCTGCTGACCAGATCCCTGCTGGCCGACACAAGGCAGCTGGCTGCCCAGCTGAGAGACAAGTTCCCCGCCGACGGCGACCACAACCTGGATAGCCTGCCTACCCTGGCCATGTCTGCTGGCGCACTGGGGGCTCTGCAGCTGCCTGGGGTGCTGACTAGACTGAGAGCCGACCTGCTGAGCTACCTGCGGCATGTGCAGTGGCTGAGAAGGGCTGGCGGCAGCAGCCTGAAAACCCTGGAACCTGAGCTGGGCACACTGCAGGCCAGACTGGACAGACTGCTGCGCAGACTGCAGCTGCTGATGAGCAGACTGGCTCTGCCCCAGCCTCCTCCTGACCCTCCTGCTCCTCCACTGGCTCCTCCAAGCTCTGCTTGGGGCGGAATTAGAGCCGCCCACGCCATTCTGGGAGGCCTGCACCTGACACTGGATTGGGCAGTGCGGGGCCTGCTGCTGCTGAAAACCAGACTGCACCACCACCATCACCACTGATAAGCTT

l-11: the amino acid sequence of the IL-11R α fusion protein (SEQ ID NO: 266):

MGWSCIILFLVATATGVHSPQAWGPPGVQYGQPGRSVKLCCPGVTAGDPVSWFRDGEPKLLQGPDSGLGHELVLAQADSTDEGTYICQTLDGALGGTVTLQLGYPPARPVVSCQAADYENFSCTWSPSQISGLPTRYLTSYRKKTVLGADSQRRSPSTGPWPCPQDPLGAARCVVHGAEFWSQYRINVTEVNPLGASTRLLDVSLQSILRPDPPQGLRVESVPGYPRRLRASWTYPASWPCQPHFLLKFRLQYRPAQHPAWSTVEPAGLEEVITDAVAGLPHAVRVSARDFLDAGTWSTWSPEAWGTPSTGGPAGQSGGGGGSGGGSGGGSVPGPPPGPPRVSPDPRAELDSTVLLTRSLLADTRQLAAQLRDKFPADGDHNLDSLPTLAMSAGALGALQLPGVLTRLRADLLSYLRHVQWLRRAGGSSLKTLEPELGTLQARLDRLLRRLQLLMSRLALPQPPPDPPAPPLAPPSSAWGGIRAAHAILGGLHLTLDWAVRGLLLLKTRLHHHHHH

Fibroblasts cultured in vitro and stimulated with super IL-11 showed upregulation of IL-11 protein expression as determined by ELISA (FIG. 43). Interestingly, no increase in IL-11RNA levels was detected in response to stimulation with super IL-11. Unlike TGF-beta 1, which increases IL-11 expression at both the DNA and protein levels, superIL-11 appears to upregulate IL-11 expression only after transcription at the protein level.

The ability of human antibodies to inhibit signaling mediated by superIL-11 was investigated.

Human atrial fibroblasts from 3 individuals were incubated with super IL-11(0.2ng/ml) for 24 hours in the presence of neutralizing anti-IL-11 antibody or isotype control antibody. After incubation, cells were stained for α SMA to determine the proportion of myofibroblasts.

After 24 hours of culture, approximately 26.5% (═ 1) of the unstimulated cells in the culture were activated fibroblasts. Stimulation with hyperil-11 resulted in a 2-fold increase in the percentage of activated fibroblasts compared to unstimulated cultures (56.4% ═ 2.13).

The results of the experiment are shown in fig. 26 and 27. Antibodies were shown to neutralize signaling mediated by superIL-11 (i.e., IL-11 trans signaling).

Monoclonal mouse IgG2A clone #22626, an anti-IL-11 antibody of cat # MAB218 was also analyzed for its ability to inhibit superIL-11 signaling. This antibody was found to be able to reduce the percentage of activated fibroblasts to 33.8% (═ 1.28).

The clone YU33-B4/YU45-G2/A3(#3) neutralized IL-11 trans signaling by super IL-11 to a greater extent than commercially available mouse anti-IL-11 antibodies (industry standard).

The results of the experimental methods described above identify antibody clones with functional properties relevant to the preclinical and clinical development of antibodies capable of inhibiting IL-11/IL-11-R signaling.

Clones YU33-B4/YU45-G2/A3(#3), YU45-E3(#16), YU45-F2(#24), YU45-F5(#39), YU46-a8(#45) and YU46-G8(#54) were identified as particularly promising candidates, showing good ability to inhibit IL-11 signaling in humans and mice, and good inhibition of IL-11 trans signaling.

6.4 affinity analysis of the antibody for human IL-11

Human anti-human IL-11 antibodies were analyzed for affinity for human IL-11 binding by ELISA assays.

Recombinant human IL-11 was obtained from Genscript and horseradish peroxidase (HRP) -conjugated anti-human IgG (Fc-specific) antibody was obtained from Sigma. Corning 96 well ELISA plates were obtained from Sigma. Pierce 3,3', 5,5' -Tetramethylbenzidine (TMB) ELISA substrate kit was obtained from Life Technologies (0.4g/mL TMB solution, 0.02% hydrogen peroxide in citrate buffer). Bovine serum albumin and sulfuric acid were obtained from Sigma. The wash buffer contained 0.05% Tween-20 in phosphate buffered saline (PBS-T). ScFv-Fc antibodies were generated as described in example 5. Purified mouse and human IgG controls were purchased from Life Technologies. Tecan Infinite 200 PRO NanoQuant was used to measure absorbance.

Cross-serial dilution analysis was performed as described by Hornbeck et al, (2015) Curr protocol Immunol 110,2.1.1-23 to determine the optimal concentrations of coating antigen, primary and secondary antibodies.

Indirect ELISA was performed to assess the 50% Effective Concentration (EC) of the primary ScFv-Fc antibody as described previously (Unverdorben et al, (2016) MAbs 8,120-128)₅₀) Binding affinity of (b). ELISA plates were coated with 1. mu.g/mL recombinant human IL-11 overnight at 4 ℃ and the remaining binding sites were blocked with 2% BSA in PBS. ScFv-Fc antibodies were diluted in PBS at 1% BSA, titrated to obtain working concentrations of 800,200,50,12.5,3.125,0.78,0.195, and 0.049ng/mL, and incubated in duplicate at room temperature for 2 hours. Antigen-antibody binding was detected with 15.625ng/mL HRP-conjugated anti-human IgG (Fc specific) antibody. After 2 h incubation with detection antibody, 100. mu.l TMB substrate was added for 15 min and 100. mu.l 2MH was used₂SO₄The color reaction was terminated. Absorbance readings were measured at 450nm and the reference wavelength was corrected at 570 nm. Individual EC50 values were determined by fitting the data with GraphPad Prism software, converting with the logarithm of the antibody concentration, and then performing non-linear regression analysis with an asymmetric (five-parameter) logistic dose-response curve.

The same materials and procedures as described above were performed to determine binding affinity to murine monoclonal anti-IL-11 antibody except that HRP-conjugated anti-mouse IgG (H & L) was used instead of HRP-conjugated anti-human IgG.

The same materials and procedures as described above were performed to determine the binding affinity of human and murine monoclonal anti-IL-11 antibodies to recombinant murine IL-11 obtained from Genscript.

The results of the ELISA assay are shown in FIGS. 28A to 28F and are used to determine the EC of the antibody₅₀Values, as shown in fig. 29.

6.5 ability to inhibit human IL-11 mediated signalling in various tissues

The ability of the antibodies to neutralize IL-11 mediated signaling and trans signaling in fibroblasts obtained from various tissues was studied, essentially as described in sections 6.1 and 6.3, except that human fibroblasts from liver, lung, kidney, eye, skin, pancreas, spleen, intestine, brain and bone marrow were used in place of cardiac atrial human fibroblasts for the experiments.

anti-IL-11 antibodies were shown to neutralize signaling in fibroblasts from various tissues, as determined by observing a relative decrease in the proportion of α SMA positive fibroblasts at the end of the 24 hour culture period in the presence of anti-IL-11 antibodies, compared to cultures in the absence of antibodies.

Example 7: light chain replacement of human anti-human IL-11 antibodies

Human IL-11 antibody affinity matures by light chain substitutions to obtain antibodies with improved affinity for IL-11.

Chain replacement for improving antibody affinity is a well-known technique in the field of antibody technology, and in Marks, antibody affinity maturation for chain replacement, methods and protocols for antibody engineering, Humana Press (2004) vol.248, pp327-343, incorporated herein by reference. Specifically, light chain substitutions are described in detail in sections 3.1 and 3.2 thereof.

The heavy chain variable region of human anti-human IL-11 antibodies was combined with a library of light chain variable region partners to identify novel VL/VH combinations with high affinity for IL-11.

A schematic of a light chain substitution is shown in figure 30. Briefly, nucleic acids encoding the VH domain of the antibody were cloned into phage display vectors comprising a repertoire of VL chains and analyzed by ELISA for binding of scFv comprising the novel VH/VL combination to human IL-11.

The scFv with the VH/VL combination that showed the strongest binding affinity for IL-11 were then analyzed for cross-reactivity with murine IL-11.

The VH/VL sequence of the scFv was then cloned into an expression vector to produce scFv-Fc (human IgG1) antibodies, the vector was transiently expressed in mammalian cells cultured in serum-free medium, and isolated by protein a purification.

Example 8: mouse monoclonal anti-human IL-11 antibody

Mouse monoclonal antibodies to human IL-11 protein were also generated, as described below.

The cDNA encoding the amino acid of human IL-11 was cloned into an expression plasmid (Aldevron GmbH, Freiburg, Germany).

Mice were immunized by intradermal administration of DNA-coated gold particles using a handheld device for particle bombardment ("gene gun"). Serum samples were collected from mice after a series of immunizations and tested on a flow cytometer for HEK cells that had been transiently transfected with a human IL-11 expression plasmid (cell surface expression of transiently transfected HEK cells to human IL-11 was confirmed with an anti-tag antibody that recognizes a tag added to the N-terminus of the IL-11 protein).

Antibody-producing cells were isolated from mice and fused with mouse myeloma cells (Ag8) according to standard procedures.

Hybridomas that produce antibodies specific for IL-11 are identified by flow cytometry screening for the ability to bind to HEK cells expressing IL-11.

Cell pellets of positive hybridoma cells were prepared using an RNA protectant (RNAlater, cat. # AM7020, ThermoFisher Scientific) and further processed to sequence the variable region of the antibody.

A total of 16 mouse monoclonal anti-human IL-11 antibodies were prepared (FIG. 31).

Example 9:functional characterization of mouse monoclonal anti-human IL-11 antibody

9.1 ability to inhibit human IL-11 mediated signalling

The ability of murine monoclonal anti-human IL-11 antibodies to inhibit human IL-11 mediated signaling was studied using the same assay as described in example 6.1 above.

The results of the experiment are shown in fig. 32 and 35. Antibodies were shown to neutralize human IL-11 mediated signaling.

Commercial monoclonal mouse anti-IL-11 antibodies (monoclonal mouse IgG 2A; clone # 22626; cat # MAB 218; R & D Systems, MN, USA) were also analyzed for their ability to inhibit human IL-11 signaling in the experiments. The antibody was found to be able to reduce the percentage of activated fibroblasts to 0.89 fold.

Clone A7(BSN-3C11) was found to neutralize human IL-11 signaling to a greater extent than commercially available mouse anti-IL-11 antibody (industry standard).

9.2 ability to inhibit IL-11 mediated signalling in mice

The ability of a murine monoclonal anti-human IL-11 antibody to inhibit signaling mediated by murine IL-11 was studied using the same assay as described in example 6.2 above, but using mouse atrial fibroblasts instead of mouse dermal fibroblasts.

The results of the experiment are shown in fig. 33 and 35. Antibodies were shown to neutralize signaling mediated by murine IL-11.

Commercial monoclonal mouse anti-IL-11 antibodies (monoclonal mouse IgG 2A; clone # 22626; cat # MAB 218; R & D Systems, MN, USA) were also analyzed for their ability to inhibit human IL-11 signaling in the experiments. This antibody was found to be able to reduce the percentage of activated fibroblasts to 43.0% (-1.44).

Several clones neutralized murine IL-11 signaling to a greater extent than commercially available mouse anti-IL-11 antibodies (industry standard): a3(BSN-2E1), A5(BSN-2G6) and A6(BSN-3C 6).

9.3 ability of mouse anti-IL-11 antibodies to inhibit IL-11 trans-signaling through IL-11 complexed with IL-11RA

The ability of mouse anti-IL-11 antibodies to inhibit signaling mediated by superIL-11 was studied.

Human atrial fibroblasts were incubated with super IL-11(0.2ng/ml) for 24 hours in the presence of anti-IL-11 antibody (2. mu.g/ml) or isotype control antibody. After incubation, cell culture supernatants were analyzed for MMP 2. Stimulation with hyperil-11 resulted in increased secretion of MMP2 compared to unstimulated cultures.

The results of the experiment are shown in fig. 34 and 35. Mouse anti-IL-11 antibodies were found to neutralize signaling mediated by hyperil-11 (i.e., IL-11 trans-signaling), and several were found to inhibit trans-signaling to a greater extent than commercial monoclonal mouse anti-IL-11 antibodies (monoclonal mouse IgG 2A; clone # 22626; cat # MAB 218; R & D Systems, MN, USA): BSN-2G6(A5), BSN-3C6(A6), BSN-5B8(A9) and BSN-7D4 (A12).

Clone BSN-3C6(a6) was identified as a particularly promising candidate for further development (highlighted in fig. 35), showing good ability to inhibit human IL-11 and mouse IL-11 mediated signaling, as well as good inhibition of IL-11 trans signaling.

9.4 screening of mouse anti-IL-11 antibodies for their ability to bind IL-11

Mouse hybridomas that produce anti-human IL-11 antibodies are subcloned, and cell culture supernatants from the subcloned hybridomas are analyzed by the "mix-measure" iQue assay for (i) ability to bind to human IL-11, and (ii) cross-reactivity to antigens other than IL-11.

Briefly, labeled control cells (which do not express IL-11 on the cell surface) and unlabeled target cells expressing human IL-11 on their surface (after transient transfection with a plasmid encoding FLAG-labeled human IL-11) are mixed with cell culture supernatant (containing mouse anti-IL-11 antibody) and secondary detection antibody (fluorescently labeled anti-mouse IgG antibody).

Cells were then analyzed for both markers (i.e., cellular marker and marker on secondary antibody) using the HTFC screening system (iQue). Detection of the secondary antibody on unlabeled IL-11 expressing cells indicates the ability of the mouse anti-IL-11 antibody to bind IL-11. Detection of secondary antibodies on labeled control cells indicates cross-reactivity of mouse anti-IL-11 antibodies to targets other than IL-11

As positive control conditions, labeled and unlabeled cells were incubated with mouse anti-FLAG-tagged antibody as primary antibody.

The results are shown in fig. 36A and 36B. Most subcloned hybridomas express antibodies that bind human IL-11 and which recognize the target with high specificity.

Clones BSN-2G6, BSN-5B8 and BSN-7F9 showed some binding to cells that do not express IL-11 and therefore may be cross-reactive to targets other than IL-11. The antibody produced by the subcloned BSN-3C11 was found not to bind to human IL-11.

13 of the 16 antibodies showed a stronger signal for binding to IL-11 than the signal of the positive control anti-tag antibody used for the tag, indicating that these antibodies bound to IL-11 with high affinity.

Example 10: chimeric and humanized forms of mouse anti-human IL-11 antibodies

The mouse/human chimeric and humanized versions of the mouse monoclonal anti-human IL-11 antibody of example 8 were prepared according to standard methods.

10.1 mouse/human chimeric antibodies

The mouse/human chimeric antibody is prepared from a mouse monoclonal anti-human IL-11 antibody, such as a human monoclonal antibody: methods and Protocols, Michael Steinitz (ed), molecular biology methods 1060, Springer Protocols, Humana Press (2014), in chapter 8 thereof.

Briefly, DNA sequences encoding the VH and VL of a hybridoma that produces a mouse anti-human IL-11 antibody are determined and combined with DNA sequences encoding human immunoglobulin constant regions to produce a mouse/human chimeric antibody sequence, wherein the chimeric mouse/human antibody is expressed in mammalian cells.

10.2 humanized antibodies

Humanized antibodies were prepared from mouse monoclonal anti-human IL-11 antibody, as human monoclonal antibody: methods and Protocols, Michael Steinitz (ed), molecular biology methods 1060, Springer Protocols, Humana Press (2014), described in chapter 7 thereof. Among these, chapter 7, section 3.1 "antibody humanization" is particularly preferred.

Briefly, DNA sequences encoding VH and VL of a mouse anti-human IL-11 antibody-producing hybridoma are determined and inserted into DNA sequences encoding human antibody variable region framework regions and immunoglobulin constant regions to produce humanized antibody sequences, which are expressed in mammalian cells.

Example 11: further biochemical analysis of anti-IL-11 antibodies

The antibodies were subjected to further biochemical analysis.

Antibodies were analyzed by BIAcore, biolayer interferometry (BLI) and MicroScale thermophoresis (MST) analysis to determine the affinity of binding to human IL-11 and mouse IL-11.

BIAcore assay of antibody affinity by Surface Plasmon Resonance (SPR) analysis such as Rich et al, Anal biochem.2008, 2 months and 1 day; 373(1): 112-20.

Such as Concepcion et al, Comb Chem high throughput screening, 9 months 2009; 12(8): 791-800 performing a biolayer interferometry analysis of antibody affinity.

Thermophoretic analysis of MicroScale antibody affinity such as Jerabek-Willemsen et al, Assay Drug Dev technol.2011 for 8 months; 9(4): 342-353.

Such as Iacob et al, J Pharm Sci.2013, 12 months; 102(12): 4315-4329 the aggregation of the antibodies was analyzed by Size Exclusion Chromatography (SEC).

Such as Haverick et al, MAbs.2014.7-8 months; 6(4): 852-8, and analyzing the hydrophobicity of the antibody by Hydrophobic Interaction Chromatography (HIC).

Such as Menzen and Friess, J Pharm Sci.2013, 2 months; 102(2): 415-28, the melting temperature of the antibody was analyzed by Differential Scanning Fluorimetry (DSF).

Example 12: inhibition of fibrosis in vivo using anti-IL-11 antibodies

The therapeutic utility of anti-human IL-11 antibodies was demonstrated in mouse models of in vivo fibrosis in a variety of different tissues. The mice used in the experiments were wild type (i.e., IL-11RA +/+) mice.

12.1 cardiac fibrosis

The pump was implanted and the mice were treated with AngII (2 mg/kg/day) for 28 days.

Neutralizing anti-IL-11 or control antibodies were administered to different groups of mice by intravenous injection. At the end of the experiment, collagen content was assessed in the atria of mice using a calorimetric-based hydroxyproline assay kit and the RNA expression levels of markers or fibrotic Col1a2, alpha SMA (ACTA2) and fibronectin (Fn1) were analyzed by qPCR.

Mice treated with the neutralizing anti-IL-11 antibody had a reduced fibrotic response in heart tissue as evidenced by reduced expression of fibrotic markers compared to mice treated with the control antibody.

12.2 renal fibrosis

A mouse model of renal fibrosis was established by in-vehicle (0.3M NaHCO)₃) Folic acid (180mg/kg) is injected into the middle abdominal membrane to induce fibrosis; control mice were given vehicle alone.

Neutralizing anti-IL-11 or control antibodies were administered to different groups of mice by intravenous injection. Kidneys were removed on day 28, weighed and fixed in 10% neutral buffered formalin, stained with masson trichrome and sirius or flash frozen for collagen determination, RNA and protein studies.

Total RNA was extracted from flash-frozen kidneys using Trizol reagent (Invitrogen) and the Qiagen tissue lyzer method, followed by RNeasy column (Qiagen) purification. cDNA was prepared using the iScriptTM cDNA synthesis kit, where each reaction contained 1. mu.g of total RNA, according to the manufacturer's instructions. Quantitative RT-PCR gene expression analysis was performed on triplicate samples using either TaqMan (applied biosystems) or Rapid SYBR Green (Qiagen) techniques in 40 cycles using StepOneNus (TM) (applied biosystems). Expression data were normalized to GAPDH mRNA expression levels and fold changes were calculated using the 2- Δ Δ Ct method. The snap-frozen kidneys were subjected to acid hydrolysis by heating in 6M HCl at a concentration of 50mg/ml (95 ℃,20 hours). The amount of total collagen in the hydrolysate was quantified using the Quickzyme total collagen assay kit (Quickzyme Biosciences) based on the colorimetric detection of hydroxyproline according to the manufacturer's instructions.

Mice treated with the neutralizing anti-IL-11 antibody had a reduced fibrotic response in kidney tissue as evidenced by reduced expression of a fibrotic marker compared to mice treated with a control antibody.

12.3 pulmonary fibrosis

Mice were treated on day 0 by intratracheal administration of bleomycin to establish a fibrotic response in the lungs (pulmonary fibrosis).

Neutralizing anti-IL-11 or control antibodies were administered to different groups of mice by intravenous injection. Mice were sacrificed on day 21 and analyzed for differences in fibrosis markers.

Mice treated with the neutralizing anti-IL-11 antibody had a reduced fibrotic response in lung tissue as evidenced by reduced expression of a fibrotic marker compared to mice treated with a control antibody.

12.4 skin fibrosis

Mice were treated on day 0 by subcutaneous administration of bleomycin to establish a fibrotic response in the skin.

Mice treated with the neutralizing anti-IL-11 antibody had a reduced fibrotic response in skin tissue as evidenced by reduced expression of fibrotic markers compared to mice treated with the control antibody.

12.5 ocular fibrosis

Mice were subjected to a trabeculectomy procedure as described in example 3.6 above to elicit a wound healing response in the eye.

Neutralizing anti-IL-11 or control antibodies were administered to different groups of mice by intravenous injection and fibrosis was monitored in ocular tissues.

Mice treated with the neutralizing anti-IL-11 antibody had a reduced fibrotic response in ocular tissues as evidenced by reduced expression of fibrotic markers compared to mice treated with the control antibody.

12.6 other tissues

The effect of neutral anti-IL-11 antibody treatment on fibrosis was also analyzed in mouse models of fibrosis in other tissues (e.g., liver, kidney, intestine), and also in models associated with multi-organ (i.e., systemic) fibrosis.

Fibrosis response was determined and compared between mice treated with neutralizing anti-IL-11 antibody and mice treated with control antibody. Mice treated with the neutralizing anti-IL-11 antibody had a reduced fibrotic response as evidenced by reduced expression of fibrotic markers compared to mice treated with the control antibody.

Example 13: in vivo treatment of cancer using anti-IL-11 antibodies

The effect of treatment with neutralizing anti-IL-11 antibodies on cancer was analyzed in a mouse model of cancer.

Models of breast, lung and gastrointestinal cancer were established in mice, treated by administration of neutralizing anti-IL-11 or control antibodies, and the development/progression of cancer was monitored.

Neutralization of the anti-cancer effect of the anti-IL-11 antibody was observed, as evidenced by a reduction in cancer symptoms and/or an increase in survival compared to mice treated with control antibodies.

Example 14: treatment of AMD using anti-IL-11 antibodies

The effect of treatment with neutralizing anti-IL-11 antibodies was studied in wet age-related macular degeneration (AMD).

Administering a neutralizing anti-IL-11 antibody to a subject having wet AMD. Under some treatment conditions, the subject is administered a VEGF antagonist therapy (e.g., ranibizumab, bevacizumab, pegaptanib, bruuzumab (brolizumab), or aflibercept), a PDGF antagonist therapy (e.g., pegpleranib), or treatment by laser photocoagulation therapy in addition to treatment with an anti-IL-11 antibody.

A reduction in wet AMD condition and/or an improvement in wet AMD symptoms is observed in a subject treated with an anti-IL-11 antibody compared to a subject not treated with an anti-IL-11 antibody.

Example 15: antibodies with light chain substitutions

Light chain replacement was performed as schematically shown in figure 30.

The following IL-11 binding antibody clones were used for light chain replacement: YU45-E03, YU45-F02, YU45-F05, YU45-G02, YU46-A08 and YU 46-G08.

The variable regions of the heavy chains were amplified by PCR, the resulting amplicons were pooled and cloned into phagemid vectors (phagemids) each containing a specific VL chain and representing the natural λ and κ light chain libraries. The phagemids containing the VH and VL were used to generate a novel antibody-phage library for selection of clones that showed binding to IL-11 under stringent conditions (i.e., antigen restriction, extensive washing steps).

Antibodies capable of binding to human IL-11 and murine IL-11 (i.e., cross-reactive antibodies) were identified by phage display, panning using biotinylated and non-biotinylated recombinant human and murine IL-11, based on the panning strategy shown in FIG. 52.

This analysis identified 66 cross-reactive antibodies (fig. 53). Sequence analysis identified 64 unique antibody clones whose amino acid sequences are shown in FIG. 50 and whose nucleotide sequences are shown in FIG. 51.

The binding signals of 64 antibody clones to human IL-11 and murine IL-11 were analyzed in an ELISA assay. The results are shown in fig. 54A and 54B.

Example 16: functional characterization of light chain replacement antibodies

54 light chain replacement antibodies were analyzed for their ability to bind IL-11 and inhibit IL-11-mediated signaling.

16.1 binding to human IL-11

Light chain-substituted anti-IL-11 antibodies were analyzed by ELISA to determine EC50 binding to human IL-11 according to standard methods. Briefly, wells of a microtiter plate were coated with recombinant human IL-11(100 ng/well), scFv-Fc containing cloned VH and VL domains was added in dilution series, and antibody binding was detected using a polyclonal antibody detection system.

The results of the ELISA assay were used to calculate the EC50 value (ng/ml) for the light chain replacement antibody clones, which are shown in FIG. 55.

16.2 ability to inhibit human IL-11 mediated signalling

To investigate the ability of the light chain replacement antibody clone to neutralize human IL-11 mediated signaling, human atrial fibroblasts were cultured in wells of a 96-well plate for 24 hours in the presence of TGF β 1(5ng/ml) in the presence of either the scFv-human IgG1-Fc form of the anti-IL-11 antibody or the human IgG1 isotype control antibody at a final concentration of 2 mg/ml. The level of the profibrotic marker MMP2 in the cell culture supernatants was then measured by ELISA. Basal MMP2 secretion by cells in culture was measured in the presence of a human IgG1 isotype control (2mg/ml) by culturing in the absence of TGF β 1.

The results of two separate experiments are shown in fig. 56A and 56B. The horizontal lines in the bar graphs indicate basal MMP2 secretion of human atrial fibroblasts cultured for 24 hours in the presence of human IgG1 isotype control antibody ('NEG' in fig. 56A and 56B), and MMP2 secretion of human atrial fibroblasts cultured for 24 hours in the presence of 5ng/ml TGF β and human IgG1 isotype control antibody ('POS' in fig. 56A and 56B), in the absence of TGF β 1 stimulation.

Light chain replacement anti-IL-11 antibodies were shown to be able to bind to human IL-11 and inhibit IL-11 mediated signaling.

Example 17: inhibition of renal fibrosis using anti-IL-11 antibodies

Similar body weight 10-12 week old littermates were injected intraperitoneally (i.p.) with folic acid (180mg kg)^-1) Support (0.3M NaHCO)₃) Inducing renal fibrosis; control mice were given vehicle alone.

anti-IL 11 antibody clone BSN-3C6 was administered one day after folate treatment and then 3 times weekly at a dose of 20 mg/kg. Mice were euthanized 28 days after injection.

Mouse plasma levels of urea and creatinine were quantified using a urea assay kit (ab83362, Abcam) and a creatinine assay kit (ab65340, Abcam), respectively, according to the manufacturer's instructions. The amount of total collagen in the kidney was quantified based on the colorimetric detection of hydroxyproline using the Quickzyme total collagen assay kit (Quickzyme Biosciences). All colorimetric determinations were performed according to the manufacturer's instructions.

Tissues were paraffin embedded and kidneys were cut to 3 μm. For paraffin sections, tissues were fixed in 10% neutral buffered formalin (Sigma-Aldrich) for 24 hours at room temperature, dehydrated and embedded in paraffin. For frozen sections, freshly cut organs were embedded with Tissue-Tek optimal cutting temperature compound (VWR International). The frozen molds were then frozen in metal beakers, cooled with isopentane in liquid nitrogen, and the sections stored at-80 ℃. Total collagen was stained with a masson trichrome staining kit (HT15, Sigma-Aldrich) according to the manufacturer's instructions. Images of the sections were captured and blue-stained areas of fibrosis were semi-quantitatively determined with ImageJ software (version 1.49). For immunohistochemistry, tissue sections were incubated with anti-ACTA 2 antibody (ab5694, Abcam). Primary anti-staining was visualized using immpres HRP anti-rabbit IgG polymer detection kit (Vector Laboratories) and ImmPACT DAB peroxidase substrate (Vector Laboratories) as chromogens. The sections were then counterstained with mayer's hematoxylin (Merck).

Fig. 58A and 58B show that mice treated with anti-IL 11 antibody were found to have significantly reduced collagen staining, indicating that anti-IL-11 antibody treatment has inhibited renal fibrosis.

Figure 59 shows that urinary albumin/creatine ratio was significantly reduced by anti-IL 11 antibody treatment, indicating a reduction in the level of kidney injury in mice treated with anti-IL-11 antibody.

FIG. 60 shows that treatment with anti-IL-11 antibody inhibits folate-induced renal fibrosis in a dose-dependent manner.

In another experiment, a mouse model of acute kidney injury was induced by Unilateral Ureteral Obstruction (UUO). Briefly, mice were treated by sham surgery or ureteral occlusion of one ureter. Mice received IgG, an anti-IL-11 antibody clone BSN-3C6(20 mg/kg; day-1, 1,3,5 of surgery), and injured kidneys ('UUO') or contralateral uninjured kidneys (Con) were harvested on the seventh post-surgery day.

Semi-quantitative assessment of tubular lesions was performed by histological analysis of tubular atrophy or tubular dilatation blinded to experimental conditions (tubular lesion score: 0, none; 1, min; 2, mild; 3, moderate; 4, severe).

FIGS. 61A and 61B show that treatment with anti-IL-11 antibody reduced renal tubular injury in a mouse model of acute renal injury.

Example 18: IL-11 and liver fibrosis

Protein expression of IL-11 in healthy and diseased livers was confirmed by Western blotting in matched samples of human livers. Matched frozen liver samples were prepared for western blotting and the level of IL11 was determined using human IL-11 antibody monoclonal mouse IgG2A clone #22626 from R & D Systems, cat # MAB 218. A film image is produced.

The results are shown in FIG. 62. Increased expression of IL-11 was detected in most diseased tissues compared to normal healthy liver.

To determine whether IL-11 expression varies with disease, an ELISA was performed on media from precision liver sections (PCLS) using the human IL-11 DuoSet 15 plate kit from R & D Systems, cat # DY 218.

Human PCLS were cleaved and incubated with media treatment after a 24 hour rest period to accommodate media plates. Samples were treated with medium only (control), LPS medium, a combination that induced the profibrotic stimulation of TGF β 1, or a combination that induced the profibrotic stimulation of TGF β 1 and the TGF β 1 inhibitor ALK 5.

The results are shown in FIG. 63. Profibrotic stimulation induces upregulation of IL-11 protein expression, and ALK5 inhibitors were found to inhibit TGF β 1 receptor signaling, which reduces IL-11 protein expression to control levels.

18.1 inhibition of hepatic fibrosis using anti-IL-11 antibodies in preclinical models of NASH

Diabetic mice (db/db; leptin receptor deficient) were maintained on either normal diet or NASH induced (methionine/choline deficient (MCD)) diet for 8 weeks. To test the efficacy of neutralizing anti-IL 11 antibodies, we administered anti-IL-11 antibody clone BSN-3C6(20mg/kg, 3 x/week, i.p.) in the last 3 weeks of the 8-week NASH diet (fig. 64A, lower panel). Total liver histology was assessed at euthanasia and the collagen content of the liver was analyzed by hydroxyproline assay.

The results are shown in FIGS. 64A and 64B. Inhibition of IL-11 mediated signaling by anti-IL-11 antibody treatment improved liver histology in a mouse model of nonalcoholic steatohepatitis (fig. 64A), as evidenced by partial restoration of liver morphology and texture in animals on the NASH diet treated with anti-IL-11 antibody compared to untreated animals on the NASH diet. It was also found that the liver from mice on the NASH diet treated with anti-IL-11 antibody had a reduced collagen content compared to untreated animals on the NASH diet (fig. 64B).

Example 19: inhibition of ocular fibrosis using anti-IL-11 antibodies

Such as Cabilllero et al, Exp Eye Res. (2009) Mar; 88(3): 367-77, anti-fibrotic effects of anti-IL-11 antibody treatment were evaluated in a mouse model of retinal fibrosis in which bruch's membrane is disrupted.

Briefly, mice were subjected to laser-induced retinal damage (4 burns per retina) and then treated by intraocular administration of antibodies (0.5 μ g of IgG control or anti-IL 11 antibody clone BSN-3C6) on days 1,7,14 and 21. Eyes were harvested on day 28 for histological analysis. The area of fibrosis in the burn area was determined using masson trichrome staining, and was unknown to the treatment.

The results are shown in fig. 65A and 65B. The area of fibrosis was significantly greater in control IgG treated mice compared to anti-IL 11 antibody treated mice.

Example 20: inhibition of skin fibrosis using anti-IL-11 antibodies

Anti-fibrotic effects of anti-IL-11 antibody treatment were analyzed in a mouse model of skin fibrosis established by subcutaneous injection of bleomycin (BLM, Sigma B2434, 50. mu.g/day).

Briefly, the fur in the middle of the back of the mouse was trimmed using scissors (-9 cm)²) And the fur was completely removed using depilatory cream. 100 μ L of bleomycin dissolved in PBS was injected subcutaneously at a concentration of 0.5mg/ml in the upper half of the injection site. Subsequently, 60 μ L of anti-IL 11 antibody clone BSN-3C6 or control IgG antibody was injected subcutaneously in the lower half of the injection site (dose ═ 15 mg/kg/day). Daily injection is givenThe injection was performed for 21 days, and animals were sacrificed one day after the final injection and analyzed histologically for dermal thickness and collagen content (by masson trichrome staining).

Fig. 66B and 66C show a significant reduction in dermal thickness in mice treated with neutralizing anti-IL-11 antibody compared to mice treated with control IgG. Increased collagen staining was also seen in the control IgG treated group (fig. 66B, middle panel).

Example 21: inhibition of cardiac fibrosis using anti-IL-11 antibodies

Anti-fibrotic effects of anti-IL-11 antibody treatment were analyzed in a mouse model of cardiac fibrosis.

Briefly, Transverse Aortic Constriction (TAC) was performed in male mice as previously described (Tarnavski, O. et al, mouse Heart surgery: comprehensive techniques for generating mouse models of human disease and their application to genomic research Physiol. genomics 16, 349-360 (2004)). Age matched mice were sham operated without TAC. Transthoracic two-dimensional doppler echocardiography was used to confirm the increase in pressure gradient (>40mm Hg), indicating successful TAC.

Mice were euthanized 2 weeks after TAC for histology and molecular evaluation. anti-IL-11 antibody clone BSN-3C6 or a control IgG antibody was administered intraperitoneally 3 times weekly at a dose of 20 mg/kg. After two weeks, the hearts were harvested and the degree of fibrosis was assessed using a masson trichrome staining kit (HT15, Sigma-Aldrich) according to the manufacturer's instructions.

The analysis results are shown in fig. 67. Mice treated with neutralizing anti-IL-11 antibody were found to have reduced levels of fibrosis in the epicardial, endocardial and perivascular regions compared to mice treated with IgG control antibody.

Claims

1. An optionally isolated antibody or antigen-binding fragment capable of binding IL-11, wherein the antibody or antigen-binding fragment is a fully human antibody or antigen-binding fragment and is capable of inhibiting IL-11 trans-signaling.

2. An optionally isolated antibody or antigen-binding fragment capable of binding IL-11 comprising the amino acid sequences i) to vi):

i)LC-CDR1:X₁X₂DX₃GX₄YX₅Y(SEQ ID NO:239)；

X₆SNX₇GX₈X₉X₁₀(SEQ ID NO:240)；

QX₁₁X₁₂SSX₁₃(SEQ ID NO:241)；

X₁₄GX₁₅IASNX₁₆(SEQ ID NO:242)；

QDVGRY (SEQ ID NO: 101); or

SLRGYY(SEQ ID NO:161)；

ii)LC-CDR2:DVX₁₇(SEQ ID NO:243)；

X₁₈NX₁₉(SEQ ID NO:244)；

X₂₀AS(SEQ ID NO:245)；

X₂₁DX₂₂(SEQ ID NO:246)；

EVX₂₃(SEQ ID NO: 247); or

DX₂₄X₂₅(SEQ ID NO:248)；

X₅₀X₅₁WDX₅₂X₅₃LX₅₄X₅₅X₅₆V(SEQ ID NO:251)；

QSYX₇₃X₇₄SX₇₅X₇₆X₇₇X₇₈(SEQ ID NO:253)；

X₇₉SYX₈₀SSX₈₁X₈₂X₈₃VX₈₄(SEQ ID NO:254)；

NSYVTGNNWA (SEQ ID NO: 169); or

DSRGRSGDHWL(SEQ ID NO:163)；

iv)HC-CDR1:GFTFSSYX₈₅(SEQ ID NO:255)；

GX₈₆X₈₇X₈₈X₈₉SYG(SEQ ID NO:256)；

X₉₀X₉₁X₉₂X₉₃X₉₄SYA(SEQ ID NO:257)；

WIFLKSYA(SEQ ID NO:204)；

VSSNSAAWN(SEQ ID NO:180)；

GGSISSSNW (SEQ ID NO: 220); or

GFTFSGAY(SEQ ID NO:183)；

v)HC-CDR2:ISYDGSX₉₅K(SEQ ID NO:258)；

IIPIFGTA(SEQ ID NO:210)；

YRSKWYN(SEQ ID NO:181)；

ISAYGNT (SEQ ID NO: 229); or

IYHSGST(SEQ ID NO:221)；

vi)HC-CDR3:AKLSGPNGVDY(SEQ ID NO:197)；

ARDX₁₀₃GYSSGWYFDY(SEQ ID NO:260)；

ARIMGYDYGDYDVVDY(SEQ ID NO:199)；

ARVGFSSWYPDLYYFDY(SEQ ID NO:205)；

X₁₃₁X₁₃₂X₁₃₃X₁₃₄RGYX₁₃₅DY(SEQ ID NO:263)；

ARITHDYGDFSDAFDI(SEQ ID NO:194)；

ARX₁₃₆GVLX₁₃₇DY(SEQ ID NO:264)；

AKGSYYFDY(SEQ ID NO:235)；

ARLYSGYPSRYYYGMDV(SEQ ID NO:206)；

ARVQSGEPESDY(SEQ ID NO:216)；

AKIGATDPLDY(SEQ ID NO:187)；

ARDLYAFDI(SEQ ID NO:185)；

ARPDDDY(SEQ ID NO:203)；

AKGGKSYYGFDY(SEQ ID NO:207)；

ARADSSAGGGPYYYGMDV(SEQ ID NO:231)；

ARVYYDSSGTQGDSFDY(SEQ ID NO:233)；

ARVVAAARSYYYYMDV(SEQ ID NO:230)；

ARGGGPYYDFWSGYYTEFDY(SEQ ID NO:224)；

ARMVNLYYGDAFDI(SEQ ID NO:218)；

ARGLITGTTP(SEQ ID NO:211)；

ARGQNVDL(SEQ ID NO:198)；

ARVQNLGGGSYYVGAFDY (SEQ ID NO: 222); or

ARLVGATADDY(SEQ ID NO:219)；

wherein, X₁Or I, X₂Or R, X₃Either V or I, X₄G, A or N, X₅N, E, K or D, X₆Or Y, X₇Is I or V, X₈Or Y, X₉N, Y or D, X₁₀Is L, Y, T or A, X₁₁G, S or I, X₁₂Is ═ S, I or V, X₁₃Y or N, X₁₄Or T, X₁₅Or N, X₁₆Y or R, X₁₇Or G, X₁₈R, I or G, X₁₉N or D, X₂₀Is A or G, X₂₁Is E, D or N, X₂₂N or D, X₂₃Is ═ S, F or N, X₂₄N or V, X₂₅H or T, X₂₆Or G, X₂₇Or T, X₂₈Or G, X₂₉Is ═ S, N, G or I, X₃₀Either T or S, X₃₁W, L, V or Q, X₃₂Or V, X₃₃Either C or S, X₃₄G or D, X₃₅Is S, Y, N or T, X₃₆Y or N, X₃₇Either T or N, X₃₈W or F, X₃₉Is V, G or L, X₄₀Or V, X₄₁Or R, X₄₂Or R, X₄₃Or R, X₄₄Or D, X₄₅Or R, X₄₆Is absent or A, X₄₇Or D, X₄₈Or R, X₄₉Is absent or P, X₅₀Is A or G, X₅₁Is A or T, X₅₂D, G or S, X₅₃Or G, X₅₄Is S, K or N, X₅₅G or A, X₅₆W, G or H, X₅₇Or Y, X₅₈Y, R or N, X₅₉Or N, X₆₀T, a or W, X₆₁Is L or T, X₆₂Y, A, W or T, X₆₃T, no or F, X₆₄Or G, X₆₅Or G, X₆₆Or G, X₆₇Or T, X₆₈Or K, X₆₉Or V, X₇₀Is absent or E, X₇₁Is absent or F, X₇₂Or K, X₇₃Either D or N, X₇₄Or Y, X₇₅Or K, S or N, X₇₆Or L, X₇₇Is I, V or W, X₇₈Or V, X₇₉Either T or N, X₈₀Either T or S, X₈₁Either T or S, X₈₂P or T, X₈₃Y or L, X₈₄Is absent or A, X₈₅Is A or G, X₈₆F or Y, X₈₇Or T, X₈₈Is L or F, X₈₉G, R, T, S or N, X₉₀G or I, X₉₁G, F or L, X₉₂Or P, X₉₃Is F or S, X₉₄Or D, X₉₅N or D, X₉₆Is L, F or D, X₉₇Y, A or L, X₉₈Or R, X₉₉Is ═ S, V or L, X₁₀₀Is equal to S, Y orP,X₁₀₁Is N, L or I, X₁₀₂Is ═ F or I, X₁₀₃Or V, X₁₀₄H or A, X₁₀₅Is ═ S, Q or F, X₁₀₆Or G, X₁₀₇Is absent or Y, X₁₀₈Or S, X₁₀₉Not, R or S, X₁₁₀Q, N or S, X₁₁₁W or Y, X₁₁₂Or is absent, Y or F, X₁₁₃Is absent or E, X₁₁₄Or W, X₁₁₅Is absent or E, X₁₁₆Is absent or P, X₁₁₇G or S, X₁₁₈Or not, R or T, X₁₁₉G, E or I, X₁₂₀Either D or H, X₁₂₁Is A or G, X₁₂₂Is A or G, X₁₂₃Is A or Y, X₁₂₄Or do not, X₁₂₅G or D, X₁₂₆Is F, M or R, X₁₂₇Is V, Y or A, X₁₂₈Is absent or F, X₁₂₉Or D, X₁₃₀Is absent or I, X₁₃₁Is absent or A, X₁₃₂Or R, X₁₃₃Is A or G, X₁₃₄R or T, X₁₃₅Is F or G, X₁₃₆Or S, X₁₃₇Or F.

3. The antibody or antigen-binding fragment of claim 2, wherein HC-CDR1 is one of VSSNSAAWN (SEQ ID NO:180), GFTFSGAY (SEQ ID NO:183), GFTFSSYG (SEQ ID NO:186), GFTFSSYA (SEQ ID NO:190), GFSFRSYG (SEQ ID NO: 193), GFTFRSYG (SEQ ID NO: 196), GFSFSSYA (SEQ ID NO: 212), WIFLKSYA (SEQ ID NO:204), GFSLNSYG (SEQ ID NO: 217), GGTFSSYA (SEQ ID NO: 209), GGSISSSNW (SEQ ID NO:220), GFSLSG (SEQ ID NO: 201), GGTFSSYA (SEQ ID NO: 209), ILPSDSYA (SEQ ID NO: 226), GYTFTSYG (SEQ ID NO:228), GFGSYG (SEQ ID NO:234) or GFSLYG (SEQ ID NO: 238).

4. The antibody or antigen-binding fragment of claim 2 or claim 3, wherein HC-CDR2 is one of YRSKWYN (SEQ ID NO:181), ISYDGSNK (SEQ ID NO:184), ISYDGSDK (SEQ ID NO: 188), IIPIFGTA (SEQ ID NO:210), IYHSGST (SEQ ID NO:221), or ISAYGNT (SEQ ID NO: 229).

5. The antibody or antigen-binding fragment of any one of claims 2 or 4, wherein HC-CDR3 is ARGTRGYFDY (SEQ ID NO: 182), ARDLYAFDI (SEQ ID NO:185), AKIGATDPLDY (SEQ ID NO:187), AKDLSGLPIIDY (SEQ ID NO: 189), ARRGYFDY (SEQ ID NO: 191), ARIAAADGMDV (SEQ ID NO: 192), ARITHDYGDFSDAFDI (SEQ ID NO: 194), AKLYSGSSNFDY (SEQ ID NO: 195), AKLSGPNGVDY (SEQ ID NO:197), ARGQNVDL (SEQ ID NO:198), ARIMGYDYGDYDVVDY (SEQ ID NO:199), ARRGYGDY (SEQ ID NO: 213), ARVGFSSWYPDLYYFDY (SEQ ID NO: 205), AKFARGVYLFDY (SEQ ID NO: 215), ARVQSGEPESDY (SEQ ID NO:216), ARMVNLYYGDAFDI (SEQ ID NO:218), ARLVGATADDY (SEQ ID NO:219), AKLSGPNGVDY (SEQ ID NO:197), ARGLITGTTP (SEQ ID NO:211), ARVQNLGGGSYYVGAFDY (SEQ ID NO: ARLHFSQYFSTIDAFDI) (SEQ ID NO: 223), ARLHFSQYFSTIDAFDI (SEQ ID NO: 223), ARDVGYSSGWYFDY (SEQ ID NO: 200), ARLAQSYSSSWYEWEPGREHAFDI (SEQ ID NO: 202), ARPDDDY (SEQ ID NO:203) AKLSGPNGVDY (SEQ ID NO:197), ARLYSGYPSRYYYGMDV (SEQ ID NO:206), AKGGKSYYGFDY (SEQ ID NO:207), ARLHSGRNWGDAFDI (SEQ ID NO: 208), ARGGGPYYDFWSGYYTEFDY (SEQ ID NO:224), ARDSGYSSGWYFDY (SEQ ID NO: 225), ARIAAAGRDAFDI (SEQ ID NO: 227), ARVVAAARSYYYYMDV (SEQ ID NO:230), ARADSSAGGGPYYYGMDV (SEQ ID NO:231), ARIGGYDDFDY (SEQ ID NO: 232), ARVYYDSSGTQGDSFDY (SEQ ID NO:233), AKGSYYFDY (SEQ ID NO:235), ARGVFDY (SEQ ID NO: 236) or ARSGVLDY (SEQ ID NO: 237).

6. The antibody or antigen-binding fragment of any one of claims 2 or 5, wherein LC-CDR1 is QDVGRY (SEQ ID NO:101), TGNIASNR (SEQ ID NO:104), SSDVGGYNY (SEQ ID NO:107), SSDVGAYNY (SEQ ID NO:110), SSDIGAYNY (SEQ ID NO:114), SSNIGSNY (SEQ ID NO:116), ISDVGGYNY (SEQ ID NO:122), SSNIGNNL (SEQ ID NO:126), SSDVGGYDY (SEQ ID NO:128), QSVSSN (SEQ ID NO:137), SSNIGNNY (SEQ ID NO:140), NVYSGSNL (SEQ ID NO:144), SSNIGSNT (SEQ ID NO:147), SRDVGGYNY (SEQ ID NO:150), SGSIASNY (SEQ ID NO:152), QIISSY (SEQ ID NO:155), SSDVGGYEY (SEQ ID NO:159), SLNIYY (SEQ ID NO:161), SSNIGSY (SEQ ID NO:167), SSNIGYY (SEQ ID NO:167), SSGYDA NO:170), QGSSSY (SEQ ID NO:173), SSDVGGYKY (SEQ ID NO:175) or SSDVGNYKY (SEQ ID NO: 178).

7. The antibody or antigen-binding fragment of any one of claims 2 or 6, wherein LC-CDR2 is one of AAS (SEQ ID NO:102), DNH (SEQ ID NO:105), DVS (SEQ ID NO:108), EVS (SEQ ID NO:111), RNN (SEQ ID NO:117), DVT (SEQ ID NO:123), DVH (SEQ ID NO:129), DVG (SEQ ID NO:133), EVN (SEQ ID NO:135), DVT (SEQ ID NO:123), GAS (SEQ ID NO:138), DNT (SEQ ID NO:141), EDD (SEQ ID NO:145), INN (SEQ ID NO:148), DDN (SEQ ID NO:153), EDN (SEQ ID NO:157), GNN (SEQ ID NO:162), RND (SEQ ID NO:165), EVF (SEQ ID NO:168) or NDN (SEQ ID NO: 171).

8. The antibody or antigen-binding fragment of any one of claims 2-7, wherein LC-CDR3 is QQYRSAPLA (SEQ ID NO:103), QSYDYSSVI (SEQ ID NO:106), SSYTSSSSWV (SEQ ID NO:109), SSYTSSNTLV (SEQ ID NO:112), SSYTSSSTVV (SEQ ID NO:113), SSYTTSSTVV (SEQ ID NO:115), AAWDGSLSGWV (SEQ ID NO:118), SSYTSSSTWV (SEQ ID NO:119), CSYAGSYTFV (SEQ ID NO:120), NSYTSSTPYV (SEQ ID NO:121), SSYAGSYTWV (SEQ ID NO:124), GSYTSSNTQV (SEQ ID NO:125), AAWDDSLSAGV (SEQ ID NO:127), SSYTSSITWV (SEQ ID NO:130), CSYAGSYTWV (SEQ ID NO:131), GSYTSSSTWV (SEQ ID NO:132), SSYTSGSTWV (SEQ ID NO:134), SSYAGTNNFVV (SEQ ID NO:136), QQYNNWPLTFGGGTKVEFK (SEQ ID NO:139), GTWDSSLSGGV (SEQ ID NO:142), SSYAGSYTWGVRRRDRADRP (SEQ ID NO:143), AAWDDSLKGHV (SEQ ID NO:146), AAWDDSLNGWV (SEQ ID NO:149), CSYADYYTWV (SEQ ID NO:151), QSYDSSNLWV (SEQ ID NO:154), QQSYSTPTWT (SEQ ID NO:156), QSYNSSKVV (SEQ ID NO:158), NSYTSSGTLVV (SEQ ID NO:160), DSRGRSGDHWL (SEQ ID NO:163), ATWDDGLSGWV (SEQ ID NO:166), NSYVTGNNWA (SEQ ID NO:169), AAWDDSLSGWV (SEQ ID NO:172), QQSYSTPLYT (SEQ ID NO:174), CSYAGNYTWL (SEQ ID NO:176), TSYSSSSTLVA (SEQ ID NO:177) or SSYTSSSTLVV (SEQ ID NO: 179).

9. The antibody or antigen-binding fragment of any one of claims 2 to 8, wherein the antibody or antigen-binding fragment has at least one heavy chain variable region comprising the following CDRs:

HC-CDR1:VSSNSAAWN(SEQ ID NO:180)

HC-CDR2:YRSKWYN(SEQ ID NO:181)

HC-CDR3:ARGTRGYFDY(SEQ ID NO:182)；

or

HC-CDR1:GFTFSGAY(SEQ ID NO:183)

HC-CDR2:ISYDGSNK(SEQ ID NO:184)

HC-CDR3:ARDLYAFDI(SEQ ID NO:185)；

Or

HC-CDR1:GFTFSSYG(SEQ ID NO:186)

HC-CDR2:ISYDGSNK(SEQ ID NO:184)

HC-CDR3:AKIGATDPLDY(SEQ ID NO:187)；

Or

HC-CDR1:GFTFSSYG(SEQ ID NO:186)

HC-CDR2:ISYDGSDK(SEQ ID NO:188)

HC-CDR3:AKDLSGLPIIDY(SEQ ID NO:189)；

Or

HC-CDR1:GFTFSSYA(SEQ ID NO:190)

HC-CDR2:ISYDGSNK(SEQ ID NO:184)

HC-CDR3:ARRGYFDY(SEQ ID NO:191)；

Or

HC-CDR1:GFTFSSYG(SEQ ID NO:186)

HC-CDR2:ISYDGSNK(SEQ ID NO:184)

HC-CDR3:ARIAAADGMDV(SEQ ID NO:192)；

Or

HC-CDR1:GFSFRSYG(SEQ ID NO:193)

HC-CDR2:ISYDGSNK(SEQ ID NO:184)

HC-CDR3:ARITHDYGDFSDAFDI(SEQ ID NO:194)；

Or

HC-CDR1:GFTFSSYG(SEQ ID NO:186)

HC-CDR2:ISYDGSNK(SEQ ID NO:184)

HC-CDR3:AKLYSGSSNFDY(SEQ ID NO:195)；

Or

HC-CDR1:GFTFRSYG(SEQ ID NO:196)

HC-CDR2:ISYDGSNK(SEQ ID NO:184)

HC-CDR3:ARITHDYGDFSDAFDI(SEQ ID NO:194)；

Or

HC-CDR1:GFTFSSYG(SEQ ID NO:186)

HC-CDR2:ISYDGSNK(SEQ ID NO:184)

HC-CDR3:AKLSGPNGVDY(SEQ ID NO:197)；

Or

HC-CDR1:GFTFSSYA(SEQ ID NO:190)

HC-CDR2:ISYDGSNK(SEQ ID NO:184)

HC-CDR3:ARGQNVDL(SEQ ID NO:198)；

Or

HC-CDR1:GFTFSSYA(SEQ ID NO:190)

HC-CDR2:ISYDGSNK(SEQ ID NO:184)

HC-CDR3:ARIMGYDYGDYDVVDY(SEQ ID NO:199)；

Or

HC-CDR1:GFSFSSYA(SEQ ID NO:212)

HC-CDR2:ISYDGSNK(SEQ ID NO:184)

HC-CDR3:ARIMGYDYGDYDVVDY(SEQ ID NO:199)；

Or

HC-CDR1:GFTFSSYG(SEQ ID NO:186)

HC-CDR2:ISYDGSNK(SEQ ID NO:184)

HC-CDR3:ARRGYGDY(SEQ ID NO:213)；

Or

HC-CDR1:WIFLKSYA(SEQ ID NO:204)

HC-CDR2:ISYDGSNK(SEQ ID NO:184)

HC-CDR3:ARVGFSSWYPDLYYFDY(SEQ ID NO:205)；

Or

HC-CDR1:GFTFSSYG(SEQ ID NO:186)

HC-CDR2:ISYDGSNK(SEQ ID NO:184)

HC-CDR3:AKFARGVYLFDY(SEQ ID NO:215)；

Or

HC-CDR1:GFTFSSYA(SEQ ID NO:190)

HC-CDR2:ISYDGSNK(SEQ ID NO:184)

HC-CDR3:ARVQSGEPESDY(SEQ ID NO:216)；

Or

HC-CDR1:GFSLNSYG(SEQ ID NO:217)

HC-CDR2:ISYDGSNK(SEQ ID NO:184)

HC-CDR3:AKLYSGSSNFDY(SEQ ID NO:195)；

Or

HC-CDR1:GFTFSSYA(SEQ ID NO:190)

HC-CDR2:ISYDGSNK(SEQ ID NO:184)

HC-CDR3:ARVGFSSWYPDLYYFDY(SEQ ID NO:205)；

Or

HC-CDR1:GFTFSSYG(SEQ ID NO:186)

HC-CDR2:ISYDGSNK(SEQ ID NO:184)

HC-CDR3:AKLSGPNGVDY(SEQ ID NO:197)；

Or

HC-CDR1:GFTFSSYA(SEQ ID NO:190)

HC-CDR2:ISYDGSNK(SEQ ID NO:184)

HC-CDR3:ARMVNLYYGDAFDI(SEQ ID NO:218)；

Or

HC-CDR1:GFTFSSYA(SEQ ID NO:190)

HC-CDR2:ISYDGSNK(SEQ ID NO:184)

HC-CDR3:ARLVGATADDY(SEQ ID NO:219)；

Or

HC-CDR1:GFTFSSYG(SEQ ID NO:186)

HC-CDR2:ISYDGSNK(SEQ ID NO:184)

HC-CDR3:AKLSGPNGVDY(SEQ ID NO:197)；

Or

HC-CDR1:GGTFSSYA(SEQ ID NO:209)

HC-CDR2:IIPIFGTA(SEQ ID NO:210)

HC-CDR3:ARGLITGTTP(SEQ ID NO:211)；

Or

HC-CDR1:GFTFSSYG(SEQ ID NO:186)

HC-CDR2:ISYDGSNK(SEQ ID NO:184)

HC-CDR3:AKLSGPNGVDY(SEQ ID NO:197)；

Or

HC-CDR1:GGSISSSNW(SEQ ID NO:220)

HC-CDR2:IYHSGST(SEQ ID NO:221)

HC-CDR3:ARVQNLGGGSYYVGAFDY(SEQ ID NO:222)；

Or

HC-CDR1:GFTFSSYG(SEQ ID NO:186)

HC-CDR2:ISYDGSNK(SEQ ID NO:184)

HC-CDR3:ARLHFSQYFSTIDAFDI(SEQ ID NO:223)；

Or

HC-CDR1:GFTFSSYA(SEQ ID NO:190)

HC-CDR2:ISYDGSNK(SEQ ID NO:184)

HC-CDR3:ARIMGYDYGDYDVVDY(SEQ ID NO:199)；

Or

HC-CDR1:GFTFSSYA(SEQ ID NO:190)

HC-CDR2:ISYDGSNK(SEQ ID NO:184)

HC-CDR3:ARDVGYSSGWYFDY(SEQ ID NO:200)；

Or

HC-CDR1:GFSLSSYG(SEQ ID NO:201)

HC-CDR2:ISYDGSNK(SEQ ID NO:184)

HC-CDR3:ARLAQSYSSSWYEWEPGREHAFDI(SEQ ID NO:202)；

Or

HC-CDR1:GFTFSSYA(SEQ ID NO:190)

HC-CDR2:ISYDGSNK(SEQ ID NO:184)

HC-CDR3:ARPDDDY(SEQ ID NO:203)；

Or

HC-CDR1:GFTFSSYG(SEQ ID NO:186)

HC-CDR2:ISYDGSNK(SEQ ID NO:184)

HC-CDR3:AKLSGPNGVDY(SEQ ID NO:197)；

Or

HC-CDR1:WIFLKSYA(SEQ ID NO:204)

HC-CDR2:ISYDGSNK(SEQ ID NO:184)

HC-CDR3:ARVGFSSWYPDLYYFDY(SEQ ID NO:205)；

Or

HC-CDR1:GFTFSSYA(SEQ ID NO:190)

HC-CDR2:ISYDGSNK(SEQ ID NO:184)

HC-CDR3:ARLYSGYPSRYYYGMDV(SEQ ID NO:206)；

Or

HC-CDR1:GFTFSSYG(SEQ ID NO:186)

HC-CDR2:ISYDGSNK(SEQ ID NO:184)

HC-CDR3:AKGGKSYYGFDY(SEQ ID NO:207)；

Or

HC-CDR1:GFTFSSYA(SEQ ID NO:190)

HC-CDR2:ISYDGSNK(SEQ ID NO:184)

HC-CDR3:ARLHSGRNWGDAFDI(SEQ ID NO:208)；

Or

HC-CDR1:GGTFSSYA(SEQ ID NO:209)

HC-CDR2:IIPIFGTA(SEQ ID NO:210)

HC-CDR3:ARGGGPYYDFWSGYYTEFDY(SEQ ID NO:224)；

Or

HC-CDR1:GFTFSSYA(SEQ ID NO:190)

HC-CDR2:ISYDGSNK(SEQ ID NO:184)

HC-CDR3:ARDSGYSSGWYFDY(SEQ ID NO:225)；

Or

HC-CDR1:GFTFSSYA(SEQ ID NO:190)

HC-CDR2:ISYDGSNK(SEQ ID NO:184)

HC-CDR3:ARDSGYSSGWYFDY(SEQ ID NO:225)；

Or

HC-CDR1:ILPSDSYA(SEQ ID NO:226)

HC-CDR2:ISYDGSNK(SEQ ID NO:184)

HC-CDR3:ARIAAAGRDAFDI(SEQ ID NO:227)；

Or

HC-CDR1:GYTFTSYG(SEQ ID NO:228)

HC-CDR2:ISAYNGNT(SEQ ID NO:229)

HC-CDR3:ARVVAAARSYYYYMDV(SEQ ID NO:230)；

Or

HC-CDR1:GGTFSSYA(SEQ ID NO:209)

HC-CDR2:IIPIFGTA(SEQ ID NO:210)

HC-CDR3:ARADSSAGGGPYYYGMDV(SEQ ID NO:231)；

Or

HC-CDR1:GFTFSSYG(SEQ ID NO:186)

HC-CDR2:ISYDGSNK(SEQ ID NO:184)

HC-CDR3:AKFARGVYLFDY(SEQ ID NO:215)；

Or

HC-CDR1:GFTFSSYG(SEQ ID NO:186)

HC-CDR2:ISYDGSNK(SEQ ID NO:184)

HC-CDR3:ARIGGYDDFDY(SEQ ID NO:232)；

Or

HC-CDR1:GFTFSSYA(SEQ ID NO:190)

HC-CDR2:ISYDGSNK(SEQ ID NO:184)

HC-CDR3:ARVYYDSSGTQGDSFDY(SEQ ID NO:233)；

Or

HC-CDR1:GFTFGSYG(SEQ ID NO:234)

HC-CDR2:ISYDGSNK(SEQ ID NO:184)

HC-CDR3:AKGSYYFDY(SEQ ID NO:235)；

Or

HC-CDR1:GFTFSSYG(SEQ ID NO:186)

HC-CDR2:ISYDGSNK(SEQ ID NO:184)

HC-CDR3:AKLSGPNGVDY(SEQ ID NO:197)；

Or

HC-CDR1:GFSLGSYG(SEQ ID NO:238)

HC-CDR2:ISYDGSNK(SEQ ID NO:184)

HC-CDR3:AKGSYYFDY(SEQ ID NO:235)；

Or

HC-CDR1:GFTFSSYA(SEQ ID NO:190)

HC-CDR2:ISYDGSNK(SEQ ID NO:184)

HC-CDR3:ARGVLFDY(SEQ ID NO:236)；

Or

HC-CDR1:GFTFSSYA(SEQ ID NO:190)

HC-CDR2:ISYDGSNK(SEQ ID NO:184)

HC-CDR3:ARSGVLDY(SEQ ID NO:237)。

10. The antibody or antigen-binding fragment of any one of claims 2 to 9, wherein the antibody or antigen-binding fragment has at least one light chain variable region comprising the following CDRs:

LC-CDR1:QDVGRY(SEQ ID NO:101)

LC-CDR2:AAS(SEQ ID NO:102)

LC-CDR3:QQYRSAPLA(SEQ ID NO:103)；

or

LC-CDR1:TGNIASNR(SEQ ID NO:104)

LC-CDR2:DNH(SEQ ID NO:105)

LC-CDR3:QSYDYSSVI(SEQ ID NO:106)；

Or

LC-CDR1:SSDVGGYNY(SEQ ID NO:107)

LC-CDR2:DVS(SEQ ID NO:108)

LC-CDR3:SSYTSSSSWV(SEQ ID NO:109)；

Or

LC-CDR1:SSDVGAYNY(SEQ ID NO:110)

LC-CDR2:EVS(SEQ ID NO:111)

LC-CDR3:SSYTSSNTLV(SEQ ID NO:112)；

Or

LC-CDR1:SSDVGGYNY(SEQ ID NO:107)

LC-CDR2:DVS(SEQ ID NO:108)

LC-CDR3:SSYTSSSTVV(SEQ ID NO:113)；

Or

LC-CDR1:SSDIGAYNY(SEQ ID NO:114)

LC-CDR2:DVS(SEQ ID NO:108)

LC-CDR3:SSYTTSSTVV(SEQ ID NO:115)；

Or

LC-CDR1:SSNIGSNY(SEQ ID NO:116)

LC-CDR2:RNN(SEQ ID NO:117)

LC-CDR3:AAWDGSLSGWV(SEQ ID NO:118)；

Or

LC-CDR1:SSDVGGYNY(SEQ ID NO:107)

LC-CDR2:DVS(SEQ ID NO:108)

LC-CDR3:SSYTSSSTWV(SEQ ID NO:119)；

Or

LC-CDR1:SSNIGSNY(SEQ ID NO:116)

LC-CDR2:RNN(SEQ ID NO:117)

LC-CDR3:AAWDGSLSGWV(SEQ ID NO:118)；

Or

LC-CDR1:SSDVGGYNY(SEQ ID NO:107)

LC-CDR2:DVS(SEQ ID NO:108)

LC-CDR3:CSYAGSYTFV(SEQ ID NO:120)；

Or

LC-CDR1:SSDVGGYNY(SEQ ID NO:107)

LC-CDR2:DVS(SEQ ID NO:108)

LC-CDR3:NSYTSSTPYV(SEQ ID NO:121)；

Or

LC-CDR1:ISDVGGYNY(SEQ ID NO:122)

LC-CDR2:DVT(SEQ ID NO:123)

LC-CDR3:SSYAGSYTWV(SEQ ID NO:124)；

Or

LC-CDR1:ISDVGGYNY(SEQ ID NO:122)

LC-CDR2:DVT(SEQ ID NO:123)

LC-CDR3:SSYAGSYTWV(SEQ ID NO:124)；

Or

LC-CDR1:SSDVGGYNY(SEQ ID NO:107)

LC-CDR2:DVS(SEQ ID NO:108)

LC-CDR3:GSYTSSNTQV(SEQ ID NO:125)；

Or

LC-CDR1:SSNIGNNL(SEQ ID NO:126)

LC-CDR2:RNN(SEQ ID NO:117)

LC-CDR3:AAWDDSLSAGV(SEQ ID NO:127)；

Or

LC-CDR1:SSDVGGYDY(SEQ ID NO:128)

LC-CDR2:DVH(SEQ ID NO:129)

LC-CDR3:SSYTSSITWV(SEQ ID NO:130)；

Or

LC-CDR1:SSDVGGYNY(SEQ ID NO:107)

LC-CDR2:DVS(SEQ ID NO:108)

LC-CDR3:CSYAGSYTWV(SEQ ID NO:131)；

Or

LC-CDR1:SSDVGGYNY(SEQ ID NO:107)

LC-CDR2:DVS(SEQ ID NO:108)

LC-CDR3:SSYTSSSTWV(SEQ ID NO:119)；

Or

LC-CDR1:SSNIGNNL(SEQ ID NO:126)

LC-CDR2:RNN(SEQ ID NO:117)

LC-CDR3:AAWDDSLSAGV(SEQ ID NO:127)；

Or

LC-CDR1:SSDVGGYNY(SEQ ID NO:107)

LC-CDR2:DVS(SEQ ID NO:108)

LC-CDR3:CSYAGSYTWV(SEQ ID NO:131)；

Or

LC-CDR1:SSDVGGYNY(SEQ ID NO:107)

LC-CDR2:DVS(SEQ ID NO:108)

LC-CDR3:SSYTSSSTVV(SEQ ID NO:113)；

Or

LC-CDR1:SSDVGGYNY(SEQ ID NO:107)

LC-CDR2:DVS(SEQ ID NO:108)

LC-CDR3:GSYTSSSTWV(SEQ ID NO:132)；

Or

LC-CDR1:SSDVGGYNY(SEQ ID NO:107)

LC-CDR2:DVG(SEQ ID NO:133)

LC-CDR3:SSYTSGSTWV(SEQ ID NO:134)；

Or

LC-CDR1:SSDVGGYNY(SEQ ID NO:107)

LC-CDR2:EVN(SEQ ID NO:135)

LC-CDR3:SSYAGTNNFVV(SEQ ID NO:136)；

Or

LC-CDR1:SSDVGGYNY(SEQ ID NO:107)

LC-CDR2:DVT(SEQ ID NO:123)

LC-CDR3:CSYAGSYTWV(SEQ ID NO:131)；

Or

LC-CDR1:QSVSSN(SEQ ID NO:137)

LC-CDR2:GAS(SEQ ID NO:138)

LC-CDR3:QQYNNWPLTFGGGTKVEFK(SEQ ID NO:139)；

Or

LC-CDR1:SSNIGNNY(SEQ ID NO:140)

LC-CDR2:DNT(SEQ ID NO:141)

LC-CDR3:GTWDSSLSGGV(SEQ ID NO:142)；

Or

LC-CDR1:ISDVGGYNY(SEQ ID NO:122)

LC-CDR2:DVT(SEQ ID NO:123)

LC-CDR3:SSYAGSYTWGVRRRDRADRP(SEQ ID NO:143)；

Or

LC-CDR1:YSNVGSNL(SEQ ID NO:144)

LC-CDR2:EDD(SEQ ID NO:145)

LC-CDR3:AAWDDSLKGHV(SEQ ID NO:146)；

Or

LC-CDR1:SSNIGSNT(SEQ ID NO:147)

LC-CDR2:INN(SEQ ID NO:148)

LC-CDR3:AAWDDSLNGWV(SEQ ID NO:149)；

Or

LC-CDR1:SSDVGGYNY(SEQ ID NO:107)

LC-CDR2:DVS(SEQ ID NO:108)

LC-CDR3:CSYAGSYTWV(SEQ ID NO:131)；

Or

LC-CDR1:SRDVGGYNY(SEQ ID NO:150)

LC-CDR2:DVS(SEQ ID NO:108)

LC-CDR3:CSYADYYTWV(SEQ ID NO:151)；

Or

LC-CDR1:SSNIGNNL(SEQ ID NO:126)

LC-CDR2:RNN(SEQ ID NO:117)

LC-CDR3:AAWDDSLSAGV(SEQ ID NO:127)；

Or

LC-CDR1:SGSIASNY(SEQ ID NO:152)

LC-CDR2:DDN(SEQ ID NO:153)

LC-CDR3:QSYDSSNLWV(SEQ ID NO:154)；

Or

LC-CDR1:QIISSY(SEQ ID NO:155)

LC-CDR2:AAS(SEQ ID NO:102)

LC-CDR3:QQSYSTPTWT(SEQ ID NO:156)；

Or

LC-CDR1:SSDVGGYNY(SEQ ID NO:107)

LC-CDR2:DVS(SEQ ID NO:108)

LC-CDR3:SSYTSSSTWV(SEQ ID NO:119)；

Or

LC-CDR1:SGSIASNY(SEQ ID NO:152)

LC-CDR2:EDN(SEQ ID NO:157)

LC-CDR3:QSYNSSKVV(SEQ ID NO:158)；

Or

LC-CDR1:SSDVGGYEY(SEQ ID NO:159)

LC-CDR2:DVS(SEQ ID NO:108)

LC-CDR3:NSYTSSGTLVV(SEQ ID NO:160)；

Or

LC-CDR1:SSDVGGYEY(SEQ ID NO:159)

LC-CDR2:DVS(SEQ ID NO:108)

LC-CDR3:NSYTSSGTLVV(SEQ ID NO:160)；

Or

LC-CDR1:SSDVGGYNY(SEQ ID NO:107)

LC-CDR2:DVS(SEQ ID NO:108)

LC-CDR3:CSYAGSYTWV(SEQ ID NO:131)；

Or

LC-CDR1:SLRGYY(SEQ ID NO:161)

LC-CDR2:GNN(SEQ ID NO:162)

LC-CDR3:DSRGRSGDHWL(SEQ ID NO:163)；

Or

LC-CDR1:SSNIGSYY(SEQ ID NO:164)

LC-CDR2:RND(SEQ ID NO:165)

LC-CDR3:ATWDDGLSGWV(SEQ ID NO:166)；

Or

LC-CDR1:SSDVGAYNY(SEQ ID NO:110)

LC-CDR2:EVF(SEQ ID NO:168)

LC-CDR3:NSYVTGNNWA(SEQ ID NO:169)；

Or

LC-CDR1:SSDVGGYNY(SEQ ID NO:107)

LC-CDR2:DVS(SEQ ID NO:108)

LC-CDR3:SSYTSSSTWV(SEQ ID NO:119)；

Or

LC-CDR1:SSNIGYDA(SEQ ID NO:170)

LC-CDR2:NDN(SEQ ID NO:171)

LC-CDR3:AAWDDSLSGWV(SEQ ID NO:172)；

Or

LC-CDR1:QGSSSY(SEQ ID NO:173)

LC-CDR2:AAS(SEQ ID NO:102)

LC-CDR3:QQSYSTPLYT(SEQ ID NO:174)；

Or

LC-CDR1:SSDVGGYKY(SEQ ID NO:175)

LC-CDR2:DVS(SEQ ID NO:108)

LC-CDR3:CSYAGNYTWL(SEQ ID NO:176)；

Or

LC-CDR1:QGSSSY(SEQ ID NO:173)

LC-CDR2:AAS(SEQ ID NO:102)

LC-CDR3:QQSYSTPLYT(SEQ ID NO:174)；

Or

LC-CDR1:SSDVGGYNY(SEQ ID NO:107)

LC-CDR2:DVS(SEQ ID NO:108)

LC-CDR3:TSYSSSSTLVA(SEQ ID NO:177)；

Or

LC-CDR1:SSDVGNYKY(SEQ ID NO:178)

LC-CDR2:DVS(SEQ ID NO:108)

LC-CDR3:SSYTSSSTLVV(SEQ ID NO:179)。

11. An optionally isolated antibody or antigen-binding fragment capable of binding IL-11, having at least one heavy chain variable region comprising the following CDRs:

HC-CDR1:VSSNSAAWN(SEQ ID NO:180)

HC-CDR2:YRSKWYN(SEQ ID NO:181)

HC-CDR3:ARGTRGYFDY(SEQ ID NO:182)；

or

HC-CDR1:GFTFSGAY(SEQ ID NO:183)

HC-CDR2:ISYDGSNK(SEQ ID NO:184)

HC-CDR3:ARDLYAFDI(SEQ ID NO:185)；

Or

HC-CDR1:GFTFSSYG(SEQ ID NO:186)

HC-CDR2:ISYDGSNK(SEQ ID NO:184)

HC-CDR3:AKIGATDPLDY(SEQ ID NO:187)；

Or

HC-CDR1:GFTFSSYG(SEQ ID NO:186)

HC-CDR2:ISYDGSDK(SEQ ID NO:188)

HC-CDR3:AKDLSGLPIIDY(SEQ ID NO:189)；

Or

HC-CDR1:GFTFSSYA(SEQ ID NO:190)

HC-CDR2:ISYDGSNK(SEQ ID NO:184)

HC-CDR3:ARRGYFDY(SEQ ID NO:191)；

Or

HC-CDR1:GFTFSSYG(SEQ ID NO:186)

HC-CDR2:ISYDGSNK(SEQ ID NO:184)

HC-CDR3:ARIAAADGMDV(SEQ ID NO:192)；

Or

HC-CDR1:GFSFRSYG(SEQ ID NO:193)

HC-CDR2:ISYDGSNK(SEQ ID NO:184)

HC-CDR3:ARITHDYGDFSDAFDI(SEQ ID NO:194)；

Or

HC-CDR1:GFTFSSYG(SEQ ID NO:186)

HC-CDR2:ISYDGSNK(SEQ ID NO:184)

HC-CDR3:AKLYSGSSNFDY(SEQ ID NO:195)；

Or

HC-CDR1:GFTFRSYG(SEQ ID NO:196)

HC-CDR2:ISYDGSNK(SEQ ID NO:184)

HC-CDR3:ARITHDYGDFSDAFDI(SEQ ID NO:194)；

Or

HC-CDR1:GFTFSSYG(SEQ ID NO:186)

HC-CDR2:ISYDGSNK(SEQ ID NO:184)

HC-CDR3:AKLSGPNGVDY(SEQ ID NO:197)；

Or

HC-CDR1:GFTFSSYA(SEQ ID NO:190)

HC-CDR2:ISYDGSNK(SEQ ID NO:184)

HC-CDR3:ARGQNVDL(SEQ ID NO:198)；

Or

HC-CDR1:GFTFSSYA(SEQ ID NO:190)

HC-CDR2:ISYDGSNK(SEQ ID NO:184)

HC-CDR3:ARIMGYDYGDYDVVDY(SEQ ID NO:199)；

Or

HC-CDR1:GFSFSSYA(SEQ ID NO:212)

HC-CDR2:ISYDGSNK(SEQ ID NO:184)

HC-CDR3:ARIMGYDYGDYDVVDY(SEQ ID NO:199)；

Or

HC-CDR1:GFTFSSYG(SEQ ID NO:186)

HC-CDR2:ISYDGSNK(SEQ ID NO:184)

HC-CDR3:ARRGYGDY(SEQ ID NO:213)；

Or

HC-CDR1:WIFLKSYA(SEQ ID NO:204)

HC-CDR2:ISYDGSNK(SEQ ID NO:184)

HC-CDR3:ARVGFSSWYPDLYYFDY(SEQ ID NO:205)；

Or

HC-CDR1:GFTFSSYG(SEQ ID NO:186)

HC-CDR2:ISYDGSNK(SEQ ID NO:184)

HC-CDR3:AKFARGVYLFDY(SEQ ID NO:215)；

Or

HC-CDR1:GFTFSSYA(SEQ ID NO:190)

HC-CDR2:ISYDGSNK(SEQ ID NO:184)

HC-CDR3:ARVQSGEPESDY(SEQ ID NO:216)；

Or

HC-CDR1:GFSLNSYG(SEQ ID NO:217)

HC-CDR2:ISYDGSNK(SEQ ID NO:184)

HC-CDR3:AKLYSGSSNFDY(SEQ ID NO:195)；

Or

HC-CDR1:GFTFSSYA(SEQ ID NO:190)

HC-CDR2:ISYDGSNK(SEQ ID NO:184)

HC-CDR3:ARVGFSSWYPDLYYFDY(SEQ ID NO:205)；

Or

HC-CDR1:GFTFSSYG(SEQ ID NO:186)

HC-CDR2:ISYDGSNK(SEQ ID NO:184)

HC-CDR3:AKLSGPNGVDY(SEQ ID NO:197)；

Or

HC-CDR1:GFTFSSYA(SEQ ID NO:190)

HC-CDR2:ISYDGSNK(SEQ ID NO:184)

HC-CDR3:ARMVNLYYGDAFDI(SEQ ID NO:218)；

Or

HC-CDR1:GFTFSSYA(SEQ ID NO:190)

HC-CDR2:ISYDGSNK(SEQ ID NO:184)

HC-CDR3:ARLVGATADDY(SEQ ID NO:219)；

Or

HC-CDR1:GFTFSSYG(SEQ ID NO:186)

HC-CDR2:ISYDGSNK(SEQ ID NO:184)

HC-CDR3:AKLSGPNGVDY(SEQ ID NO:197)；

Or

HC-CDR1:GGTFSSYA(SEQ ID NO:209)

HC-CDR2:IIPIFGTA(SEQ ID NO:210)

HC-CDR3:ARGLITGTTP(SEQ ID NO:211)；

Or

HC-CDR1:GFTFSSYG(SEQ ID NO:186)

HC-CDR2:ISYDGSNK(SEQ ID NO:184)

HC-CDR3:AKLSGPNGVDY(SEQ ID NO:197)；

Or

HC-CDR1:GGSISSSNW(SEQ ID NO:220)

HC-CDR2:IYHSGST(SEQ ID NO:221)

HC-CDR3:ARVQNLGGGSYYVGAFDY(SEQ ID NO:222)；

Or

HC-CDR1:GFTFSSYG(SEQ ID NO:186)

HC-CDR2:ISYDGSNK(SEQ ID NO:184)

HC-CDR3:ARLHFSQYFSTIDAFDI(SEQ ID NO:223)；

Or

HC-CDR1:GFTFSSYA(SEQ ID NO:190)

HC-CDR2:ISYDGSNK(SEQ ID NO:184)

HC-CDR3:ARIMGYDYGDYDVVDY(SEQ ID NO:199)；

Or

HC-CDR1:GFTFSSYA(SEQ ID NO:190)

HC-CDR2:ISYDGSNK(SEQ ID NO:184)

HC-CDR3:ARDVGYSSGWYFDY(SEQ ID NO:200)；

Or

HC-CDR1:GFSLSSYG(SEQ ID NO:201)

HC-CDR2:ISYDGSNK(SEQ ID NO:184)

HC-CDR3:ARLAQSYSSSWYEWEPGREHAFDI(SEQ ID NO:202)；

Or

HC-CDR1:GFTFSSYA(SEQ ID NO:190)

HC-CDR2:ISYDGSNK(SEQ ID NO:184)

HC-CDR3:ARPDDDY(SEQ ID NO:203)；

Or

HC-CDR1:GFTFSSYG(SEQ ID NO:186)

HC-CDR2:ISYDGSNK(SEQ ID NO:184)

HC-CDR3:AKLSGPNGVDY(SEQ ID NO:197)；

Or

HC-CDR1:WIFLKSYA(SEQ ID NO:204)

HC-CDR2:ISYDGSNK(SEQ ID NO:184)

HC-CDR3:ARVGFSSWYPDLYYFDY(SEQ ID NO:205)；

Or

HC-CDR1:GFTFSSYA(SEQ ID NO:190)

HC-CDR2:ISYDGSNK(SEQ ID NO:184)

HC-CDR3:ARLYSGYPSRYYYGMDV(SEQ ID NO:206)；

Or

HC-CDR1:GFTFSSYG(SEQ ID NO:186)

HC-CDR2:ISYDGSNK(SEQ ID NO:184)

HC-CDR3:AKGGKSYYGFDY(SEQ ID NO:207)；

Or

HC-CDR1:GFTFSSYA(SEQ ID NO:190)

HC-CDR2:ISYDGSNK(SEQ ID NO:184)

HC-CDR3:ARLHSGRNWGDAFDI(SEQ ID NO:208)；

Or

HC-CDR1:GGTFSSYA(SEQ ID NO:209)

HC-CDR2:IIPIFGTA(SEQ ID NO:210)

HC-CDR3:ARGGGPYYDFWSGYYTEFDY(SEQ ID NO:224)；

Or

HC-CDR1:GFTFSSYA(SEQ ID NO:190)

HC-CDR2:ISYDGSNK(SEQ ID NO:184)

HC-CDR3:ARDSGYSSGWYFDY(SEQ ID NO:225)；

Or

HC-CDR1:GFTFSSYA(SEQ ID NO:190)

HC-CDR2:ISYDGSNK(SEQ ID NO:184)

HC-CDR3:ARDSGYSSGWYFDY(SEQ ID NO:225)；

Or

HC-CDR1:ILPSDSYA(SEQ ID NO:226)

HC-CDR2:ISYDGSNK(SEQ ID NO:184)

HC-CDR3:ARIAAAGRDAFDI(SEQ ID NO:227)；

Or

HC-CDR1:GYTFTSYG(SEQ ID NO:228)

HC-CDR2:ISAYNGNT(SEQ ID NO:229)

HC-CDR3:ARVVAAARSYYYYMDV(SEQ ID NO:230)；

Or

HC-CDR1:GGTFSSYA(SEQ ID NO:209)

HC-CDR2:IIPIFGTA(SEQ ID NO:210)

HC-CDR3:ARADSSAGGGPYYYGMDV(SEQ ID NO:231)；

Or

HC-CDR1:GFTFSSYG(SEQ ID NO:186)

HC-CDR2:ISYDGSNK(SEQ ID NO:184)

HC-CDR3:AKFARGVYLFDY(SEQ ID NO:215)；

Or

HC-CDR1:GFTFSSYG(SEQ ID NO:186)

HC-CDR2:ISYDGSNK(SEQ ID NO:184)

HC-CDR3:ARIGGYDDFDY(SEQ ID NO:232)；

Or

HC-CDR1:GFTFSSYA(SEQ ID NO:190)

HC-CDR2:ISYDGSNK(SEQ ID NO:184)

HC-CDR3:ARVYYDSSGTQGDSFDY(SEQ ID NO:233)；

Or

HC-CDR1:GFTFGSYG(SEQ ID NO:234)

HC-CDR2:ISYDGSNK(SEQ ID NO:184)

HC-CDR3:AKGSYYFDY(SEQ ID NO:235)；

Or

HC-CDR1:GFTFSSYG(SEQ ID NO:186)

HC-CDR2:ISYDGSNK(SEQ ID NO:184)

HC-CDR3:AKLSGPNGVDY(SEQ ID NO:197)；

Or

HC-CDR1:GFSLGSYG(SEQ ID NO:238)

HC-CDR2:ISYDGSNK(SEQ ID NO:184)

HC-CDR3:AKGSYYFDY(SEQ ID NO:235)；

Or

HC-CDR1:GFTFSSYA(SEQ ID NO:190)

HC-CDR2:ISYDGSNK(SEQ ID NO:184)

HC-CDR3:ARGVLFDY(SEQ ID NO:236)；

Or

HC-CDR1:GFTFSSYA(SEQ ID NO:190)

HC-CDR2:ISYDGSNK(SEQ ID NO:184)

HC-CDR3 ARSGVLDY (SEQ ID NO: 237); and

12. An optionally isolated antibody or antigen-binding fragment capable of binding IL-11 comprising light and heavy chain variable region sequences, wherein:

the light chain includes LC-CDR1, LC-CDR2, LC-CDR3 having at least 85% overall sequence identity to LC-CDR1, LC-CDR1: x₁X₂DX₃GX₄YX₅Y(SEQ ID NO:239)，X₆SNX₇GX₈X₉X₁₀(SEQ ID NO:240),QX₁₁X₁₂SSX₁₃(SEQ ID NO:241),X₁₄GX₁₅IASNX₁₆(SEQ ID NO:242),QDVGRY (SEQ ID NO:101), or SLRGYY (SEQ ID NO: 161); LC-CDR 2: DVX₁₇(SEQ ID NO:243),X₁₈NX₁₉(SEQ ID NO:244),X₂₀AS(SEQ ID NO:245),X₂₁DX₂₂(SEQ ID NO:246),EVX₂₃(SEQ ID NO:247), or DX₂₄X₂₅(SEQ ID NO: 248); LC-CDR3: x₂₆SYTX₂₇X₂₈X₂₉X₃₀X₃₁VX₃₂(SEQ ID NO:249),X₃₃SYAX₃₄X₃₅X₃₆X₃₇X₃₈X₃₉X₄ ₀X₄₁X₄₂X₄₃X₄₄X₄₅X₄₆X₄₇X₄₈X₄₉(SEQ ID NO:250),X₅₀X₅₁WDX₅₂X₅₃LX₅₄X₅₅X₅₆V(SEQ ID NO:251),QQX₅₇X₅₈X₅₉PX₆₀X₆₁X₆₂X₆₃X₆₄X₆₅X₆₆X₆₇X₆₈X₆₉X₇₀X₇₁X₇₂(SEQ ID NO:252),QSYX₇₃X₇₄SX₇₅X₇₆X₇₇X₇₈(SEQ ID NO:253),X₇₉SYX₈₀SSX₈₁X₈₂X₈₃VX₈₄(SEQ ID NO:254), NSYVTGNNWA (SEQ ID NO:169), or DSRGRSGDHWL (SEQ ID NO: 163); and

the heavy chain includes HC-CDR1, HC-CDR2, HC-CDR3, which has at least 85% overall sequence identity with HC-CDR1, HC-CDR 1: GFTFSSYX₈₅(SEQ ID NO:255),GX₈₆X₈₇X₈₈X₈₉SYG(SEQ ID NO:256),X₉₀X₉₁X₉₂X₉₃X₉₄One of SYA (SEQ ID NO:257), WIFLKSYA (SEQ ID NO:204), VSSNSAAWN (SEQ ID NO:180), GGSISSSNW (SEQ ID NO:220), or GFTFSGAY (SEQ ID NO: 183); HC-CDR 2: ISYDGSX₉₅K (SEQ ID NO:258), IIPIFGTA (SEQ ID NO:210), YRSKWYN (SEQ ID NO:181), ISAYGNT (SEQ ID NO:229), or IYHSGST (SEQ ID NO: 221); HC-CDR3: AKLSGPNGVDY (SEQ ID NO:197), AKX₉₆X₉₇X₉₈GX₉₉X₁₀₀X₁₀₁X₁₀₂DY(SEQ ID NO:259),ARDX₁₀₃GYSSGWYFDY(SEQ ID NO:260),ARLX₁₀₄X₁₀₅X₁₀₆X₁₀₇X₁₀₈X₁₀₉X₁₁₀X₁₁₁X₁₁₂X₁₁₃X₁₁₄X₁₁₅X₁₁₆X₁₁₇X₁₁₈X₁₁₉X₁₂₀AFDI(SEQ ID NO:261),ARIMGYDYGDYDVVDY(SEQ ID NO:199),ARIX₁₂₁X₁₂₂X₁₂₃X₁₂₄X₁₂₅X₁₂₆DX₁₂₇X₁₂₈X₁₂₉X₁₃₀(SEQ ID NO:262),ARVGFSSWYPDLYYFDY(SEQ ID NO:205),X₁₃₁X₁₃₂X₁₃₃X₁₃₄RGYX₁₃₅DY(SEQ ID NO:263),ARITHDYGDFSDAFDI(SEQ ID NO:194),ARX₁₃₆GVLX₁₃₇DY (SEQ ID NO:264), AKGSYYFDY (SEQ ID NO:235), ARLYSGYPSRYYYGMDV (SEQ ID NO:206), ARVQSGEPESDY (SEQ ID NO:216), AKIGATDPLDY (SEQ ID NO:187), ARDLYAFDI (SEQ ID NO:185), ARPDDDY (SEQ ID NO:203), AKGGKSYYGFDY (SEQ ID NO:207), ARADSSAGGGPYYYGMDV (SEQ ID NO:231), ARVYYDSSGTQGDSFDY (SEQ ID NO:233), ARVVAAARSYYYYMDV (SEQ ID NO:230), ARGGGPYYDFWSGYYTEFDY (SEQ ID NO:224), ARMVNLYYGDAFDI (SEQ ID NO:218), ARGLITGTTP (SEQ ID NO:211), ARGQNVDL (SEQ ID NO:198), ARVQNLGGGSYYVGAFDY (SEQ ID NO:222), or ARLVGATADDY (SEQ ID NO: 219);

13. An optionally isolated antibody or antigen-binding fragment capable of binding IL-11 comprising light and heavy chain variable region sequences, wherein:

14. An optionally isolated antibody or antigen-binding fragment capable of binding IL-11, which is capable of inhibiting IL-11 trans-signaling, optionally wherein the antibody or antigen-binding fragment is the antibody or antigen-binding fragment of any one of claims 2-13.

15. The antibody or antigen-binding fragment of any one of claims 1 to 14, wherein the antibody or antigen-binding fragment is conjugated to a drug moiety or detectable moiety.

16. An optionally isolated in vitro complex comprising the antibody or antigen-binding fragment of any one of claims 1-15 bound to IL-11.

17. A composition comprising the antibody or antigen-binding fragment of any one of claims 1-15, and at least one pharmaceutically acceptable carrier.

18. An isolated nucleic acid encoding the antibody or antigen-binding fragment of any one of claims 1-15.

19. A vector comprising the nucleic acid of claim 18.

20. A host cell comprising the vector of claim 19.

21. A method of making the antibody or antigen-binding fragment of any one of claims 1-15, comprising culturing the host cell of claim 20 under conditions suitable for expression of the antibody or antigen-binding fragment, and recovering the antibody or antigen-binding fragment.

22. An antibody, antigen-binding fragment or composition according to any one of claims 1 to 15 or 17 for use in a method of therapy or medical treatment.

23. Use of an antibody, antigen-binding fragment or composition according to any one of claims 1 to 15 or 17 for the treatment or prevention of fibrosis, or a disease/disorder characterised by fibrosis.

24. An antibody, antigen-binding fragment or composition according to any one of claims 1 to 15 or 17 for use in the treatment of cancer.

25. Use of an antibody, antigen-binding fragment, or composition of any one of claims 1-15 or 17 in the manufacture of a medicament for treating or preventing fibrosis or a disease/disorder characterized by fibrosis.

26. Use of an antibody, antigen-binding fragment, or composition of any one of claims 1-15 or 17 in the manufacture of a medicament for the treatment or prevention of cancer.

27. A method of treating fibrosis comprising administering the antibody, antigen-binding fragment or composition of any one of claims 1-15 or 17 to an individual having fibrosis or a disease/disorder characterized by fibrosis.

28. A method of treating cancer comprising administering to an individual having cancer the antibody, antigen-binding fragment, or composition of any one of claims 1-15 or 17.

29. An antibody or antigen-binding fragment for use in a method of treating a disease, wherein IL-11 mediated signaling is associated with the pathology of the disease, wherein said antibody or antigen-binding fragment is capable of inhibiting IL-11 trans signaling.

30. Use of an antibody or antigen-binding fragment in the manufacture of a medicament for treating a disease in which IL-11 mediated signaling is implicated in the pathology of the disease, wherein the antibody or antigen-binding fragment is capable of inhibiting IL-11 trans signaling.

31. A method of treating a disease in which IL-11 mediated signaling is associated with the pathology of the disease, comprising administering to an individual having the disease an antibody or antigen binding fragment, wherein said antibody or antigen binding fragment is capable of inhibiting IL-11 trans signaling.

32. A method comprising contacting a sample containing or suspected of containing IL-11 with the antibody or antigen-binding fragment of any one of claims 1-15 and detecting the formation of a complex of the antibody or antigen-binding fragment and IL-11.

33. A method of diagnosing a disease or disorder in an individual, comprising contacting a sample from an individual with the antibody or antigen-binding fragment of any one of claims 1-15 in vitro and detecting the formation of a complex of the antibody or antigen-binding fragment and IL-11.

34. A method of selecting or stratifying an individual for treatment with an IL-11 targeting agent, said method comprising contacting a sample from an individual in vitro with an antibody or antigen-binding fragment according to any one of claims 1 to 15 and detecting the formation of a complex of said antibody or antigen-binding fragment and IL-11.

35. Use of an antibody or antigen-binding fragment according to any one of claims 1 to 15 for the detection of IL-11 in vitro or in vivo.

36. Use of an antibody or antigen-binding fragment according to any one of claims 1 to 15 as a diagnostic or prognostic agent in vitro or in vivo.

37. An optionally isolated antibody or antigen-binding fragment capable of binding IL-11 comprising the amino acid sequences of sequences i) to vi):

ii)LC-CDR2:DVX₁₅₇(SEQ ID NO:402) or X₁₅₈AS(SEQ ID NO:403)；

iii)LC-CDR3:X₁₅₉SYAGX₁₆₀X₁₆₁X₁₆₂WX₁₆₃(SEQ ID NO:404),SSYTX₁₆₄X₁₆₅X₁₆₆X₁₆₇WV(SEQ ID NO:405),QQSYSX₁₆₈PX₁₆₉WT(SEQ ID NO:406),SSFX₁₇₀X₁₇₁SX₁₇₂X₁₇₃WV(SEQ ID NO:407),NSYTSGSTWV(SEQ ID NO:362),ASYTRSSVWV (SEQ ID NO:334), QQSSTSPTWA (SEQ ID NO:357), or SSYRSGSTLGVRRRDQADRPR (SEQ ID NO: 282);

iv)HC-CDR1:GFTFX₁₇₄SYX₁₇₅(SEQ ID NO:409)；

v)HC-CDR2:ISYDGSNX₁₇₆(SEQ ID NO:410)；

38. The antibody or antigen-binding fragment of claim 37, wherein HC-CDR1 is one of GFTFSSYG (SEQ ID NO:186), GFTFSSYA (SEQ ID NO:190) or GFTFGSYG (SEQ ID NO: 234).

39. The antibody or antigen-binding fragment of claim 37 or claim 38, wherein the HC-CDR2 is one of ISYDGSNK (SEQ ID NO:184) or ISYDGSNR (SEQ ID NO: 381).

40. The antibody or antigen-binding fragment of any one of claims 37 to 39, wherein HC-CDR3 is one of AKIGATDPLDY (SEQ ID NO:187), ARIMGYDYGDYDVVDY (SEQ ID NO:199), AKGGKSYYGFDY (SEQ ID NO:207), AKGSYYFDY (SEQ ID NO:235) or AKLSGPNGVDY (SEQ ID NO: 197).

41. The antibody or antigen-binding fragment of any one of claims 37 to 40, wherein LC-CDR1 is SSDVGGYNF (SEQ ID NO:294), SSDVGGYEY (SEQ ID NO:159), SRDVGGYNY (SEQ ID NO:150), NSDVGGYNY (SEQ ID NO:300), SSDVGGYDY (SEQ ID NO:128), SSDVGGYNY (SEQ ID NO:107), ISDVGGYNY (SEQ ID NO:122), SSDVGDYDY (SEQ ID NO:317), SSDVAGYNY (SEQ ID NO:330), SSDVGTYNY (SEQ ID NO:344), NTDVGAYNY (SEQ ID NO:272), SNDIGAYNY (SEQ ID NO:306), SSDVGAYNY (SEQ ID NO:110), SSDIGVYNY (SEQ ID NO:347), SSDIGGYNY (SEQ ID NO:326), SSDVGAYDY (SEQ ID NO:333), GSDVGAYDY (SEQ ID NO:322), SGDVGTYNY (SEQ ID NO:298), SGDVGTYDY (SEQ ID NO:302), QINSY (SEQ ID NO:352), QIISSY (SEQ ID NO:155), QSFSSSY (SEQ ID NO:356), QSVSSSY (SEQ ID NO:367), RSDIGGYDY (SEQ ID NO:290), RRDVGGYDF (SEQ ID NO:339), SSNVGGYNY (SEQ ID NO:284), GSNVGGYNY (SEQ ID NO:349) or QSVNSAY (SEQ ID NO: 359).

42. The antibody or antigen-binding fragment of any one of claims 37-41, wherein the LC-CDR2 is one of DVS (SEQ ID NO:108), DVV (SEQ ID NO:275), DVT (SEQ ID NO:123), DVD (SEQ ID NO:295), DVN (SEQ ID NO:291), DVG (SEQ ID NO:133), AAS (SEQ ID NO:102), or GAS (SEQ ID NO: 138).

43. The antibody or antigen-binding fragment of any one of claims 37-42, wherein LC-CDR3 is CSYAGSYTWV (SEQ ID NO:131), SSYAGSYTWV (SEQ ID NO:124), CSYAGSYSWV (SEQ ID NO:273), CSYAGGYTWV (SEQ ID NO:276), NSYAGSYTWV (SEQ ID NO:278), CSYAGSYVWV (SEQ ID NO:285), CSYAGRYTWI (SEQ ID NO:296), CSYAGRYTWM (SEQ ID NO:336), CSYAGTYTWV (SEQ ID NO:340), CSYAGFYTWV (SEQ ID NO:345), CSYAGSHIWV (SEQ ID NO:308), CSYAGRYTWV (SEQ ID NO:313), CSYAGNYTWM (SEQ ID NO:315), CSYAGSYTWI (SEQ ID NO:324), ASYAGNYNWV (SEQ ID NO:304), SSYAGGYTWV (SEQ ID NO:364), SSYTNSRTWV (SEQ ID NO:292), SSYTSNTTWV (SEQ ID NO:311), SSYTSSTTWV (SEQ ID NO:320), SSYTSSSSWV (SEQ ID NO:109), SSYTSSISWV (SEQ ID NO:288), SSYTSSITWV (SEQ ID NO:130), QQSYSTPSWT (SEQ ID NO:354), QQSYSDPRWT (SEQ ID NO:360), QQSYSTPTWT (SEQ ID NO:156), SSFTTSIAWV (SEQ ID NO:268), SSFTSSTTWV (SEQ ID NO:281), SSFATSISWV (SEQ ID NO:408), NSYTSGSTWV (SEQ ID NO:362), ASYTRSSVWV (SEQ ID NO:334), QQSSTSPTWA (SEQ ID NO:357) or SSYRSGSTLGVRRRDQADRPR (SEQ ID NO: 282).

44. The antibody or antigen-binding fragment of any one of claims 37 to 43, wherein the antibody or antigen-binding fragment has at least one heavy chain variable region comprising the following CDRs:

HC-CDR1:GFTFSSYG(SEQ ID NO:186)

HC-CDR2:ISYDGSNK(SEQ ID NO:184)

HC-CDR3:AKIGATDPLDY(SEQ ID NO:187)；

or

HC-CDR1:GFTFSSYA(SEQ ID NO:190)

HC-CDR2:ISYDGSNK(SEQ ID NO:184)

HC-CDR3:ARIMGYDYGDYDVVDY(SEQ ID NO:199)；

Or

HC-CDR1:GFTFGSYG(SEQ ID NO:234)

HC-CDR2:ISYDGSNK(SEQ ID NO:184)

HC-CDR3:AKIGATDPLDY(SEQ ID NO:187)；

Or

HC-CDR1:GFTFSSYG(SEQ ID NO:186)

HC-CDR2:ISYDGSNR(SEQ ID NO:381)

HC-CDR3:AKIGATDPLDY(SEQ ID NO:187)；

Or

HC-CDR1:GFTFSSYG(SEQ ID NO:186)

HC-CDR2:ISYDGSNK(SEQ ID NO:184)

HC-CDR3:ARIMGYDYGDYDVVDY(SEQ ID NO:199)；

Or

HC-CDR1:GFTFSSYG(SEQ ID NO:186)

HC-CDR2:ISYDGSNK(SEQ ID NO:184)

HC-CDR3:AKGGKSYYGFDY(SEQ ID NO:207)；

Or

HC-CDR1:GFTFGSYG(SEQ ID NO:234)

HC-CDR2:ISYDGSNK(SEQ ID NO:184)

HC-CDR3:AKGSYYFDY(SEQ ID NO:235)；

Or

HC-CDR1:GFTFSSYG(SEQ ID NO:186)

HC-CDR2:ISYDGSNK(SEQ ID NO:184)

HC-CDR3:AKLSGPNGVDY(SEQ ID NO:197).

45. The antibody or antigen-binding fragment of any one of claims 37 to 44, wherein the antibody or antigen-binding fragment has at least one light chain variable region comprising the following CDRs:

LC-CDR1:SSDVGAYNY(SEQ ID NO:110)

LC-CDR2:DVS(SEQ ID NO:108)

LC-CDR3:SSFTTSIAWV(SEQ ID NO:268)；

or

LC-CDR1:SSDVGGYNY(SEQ ID NO:107)

LC-CDR2:DVS(SEQ ID NO:108)

LC-CDR3: CSYAGSYTWV (SEQ ID NO: 131); or

LC-CDR1:SSDVGGYNY(SEQ ID NO:107)

LC-CDR2:DVS(SEQ ID NO:108)

LC-CDR3:SSYAGSYTWV(SEQ ID NO:124)；

Or

LC-CDR1:NTDVGAYNY(SEQ ID NO:272)

LC-CDR2:DVS(SEQ ID NO:108)

LC-CDR3:CSYAGSYSWV(SEQ ID NO:273)；

Or

LC-CDR1:SSDVGGYNY(SEQ ID NO:107)

LC-CDR2:DVV(SEQ ID NO:275)

LC-CDR3:CSYAGGYTWV(SEQ ID NO:276)；

Or

LC-CDR1:SSDVGGYNY(SEQ ID NO:107)

LC-CDR2:DVS(SEQ ID NO:108)

LC-CDR3:NSYAGSYTWV(SEQ ID NO:278)；

Or

LC-CDR1:SRDVGGYNY(SEQ ID NO:150)

LC-CDR2:DVS(SEQ ID NO:108)

LC-CDR3:CSYAGSYTWV(SEQ ID NO:131)；

Or

LC-CDR1:SSDVGGYNY(SEQ ID NO:107)

LC-CDR2:DVS(SEQ ID NO:108)

LC-CDR3:SSFTSSTTWV(SEQ ID NO:281)；

Or

LC-CDR1:SSDVGGYNY(SEQ ID NO:107)

LC-CDR2:DVS(SEQ ID NO:108)

LC-CDR3:SSYRSGSTLGVRRRDQADRPR(SEQ ID NO:282)；

Or

LC-CDR1:SSNVGGYNY(SEQ ID NO:284)

LC-CDR2:DVS(SEQ ID NO:108)

LC-CDR3:CSYAGSYVWV(SEQ ID NO:285)；

Or

LC-CDR1:SSDVGGYNY(SEQ ID NO:107)

LC-CDR2:DVT(SEQ ID NO:123)

LC-CDR3:CSYAGGYTWV(SEQ ID NO:276)；

Or

LC-CDR1:SSDVGGYNY(SEQ ID NO:107)

LC-CDR2:DVS(SEQ ID NO:108)

LC-CDR3:SSYTSSISWV(SEQ ID NO:288)；

Or

LC-CDR1:RSDIGGYDY(SEQ ID NO:290)

LC-CDR2:DVN(SEQ ID NO:291)

LC-CDR3:SSYTSSITWV(SEQ ID NO:130)；

Or

LC-CDR1:SSDVGGYNY(SEQ ID NO:107)

LC-CDR2:DVS(SEQ ID NO:108)

LC-CDR3:SSYTNSRTWV(SEQ ID NO:292)；

Or

LC-CDR1:SSDVGGYNF(SEQ ID NO:294)

LC-CDR2:DVD(SEQ ID NO:295)

LC-CDR3:CSYAGRYTWI(SEQ ID NO:296)；

Or

LC-CDR1:SGDVGTYNY(SEQ ID NO:298)

LC-CDR2:DVS(SEQ ID NO:108)

LC-CDR3:NSYAGSYTWV(SEQ ID NO:278)；

Or

LC-CDR1:NSDVGGYNY(SEQ ID NO:300)

LC-CDR2:DVS(SEQ ID NO:108)

LC-CDR3:CSYAGSYTWV(SEQ ID NO:131)；

Or

LC-CDR1:SGDVGTYDY(SEQ ID NO:302)

LC-CDR2:DVS(SEQ ID NO:108)

LC-CDR3:NSYAGSYTWV(SEQ ID NO:278)；

Or

LC-CDR1:SSNVGGYNY(SEQ ID NO:284)

LC-CDR2:DVS(SEQ ID NO:108)

LC-CDR3:ASYAGNYNWV(SEQ ID NO:304)；

Or

LC-CDR1:SNDIGAYNY(SEQ ID NO:306)

LC-CDR2:DVN(SEQ ID NO:291)

LC-CDR3:CSYAGSYSWV(SEQ ID NO:273)；

Or

LC-CDR1:SSDVGGYNY(SEQ ID NO:107)

LC-CDR2:DVT(SEQ ID NO:123)

LC-CDR3:CSYAGSHIWV(SEQ ID NO:308)；

Or

LC-CDR1:SSDVGGYNY(SEQ ID NO:107)

LC-CDR2:DVS(SEQ ID NO:108)

LC-CDR3:CSYAGSYSWV(SEQ ID NO:273)；

Or

LC-CDR1:SSDVGGYDY(SEQ ID NO:128)

LC-CDR2:DVT(SEQ ID NO:123)

LC-CDR3:SSYTSNTTWV(SEQ ID NO:311)；

Or

LC-CDR1:SSDVGGYDY(SEQ ID NO:128)

LC-CDR2:DVT(SEQ ID NO:123)

LC-CDR3:CSYAGRYTWV(SEQ ID NO:313)；

Or

LC-CDR1:SSDVGGYNY(SEQ ID NO:107)

LC-CDR2:DVS(SEQ ID NO:108)

LC-CDR3:CSYAGNYTWM(SEQ ID NO:315)；

Or

LC-CDR1:SSDVGDYDY(SEQ ID NO:317)

LC-CDR2:DVT(SEQ ID NO:123)

LC-CDR3:CSYAGSYTWV(SEQ ID NO:131)；

Or

LC-CDR1:SSDVGGYNY(SEQ ID NO:107)

LC-CDR2:DVS(SEQ ID NO:108)

LC-CDR3:SSYTSSTTWV(SEQ ID NO:320)；

Or

LC-CDR1:GSDVGAYDY(SEQ ID NO:322)

LC-CDR2:DVN(SEQ ID NO:291)

LC-CDR3:SSFATSISWV(SEQ ID NO:408)；

Or

LC-CDR1:SSDVGGYNY(SEQ ID NO:107)

LC-CDR2:DVT(SEQ ID NO:123)

LC-CDR3:CSYAGSYTWI(SEQ ID NO:324)；

Or

LC-CDR1:SSDIGGYNY(SEQ ID NO:326)

LC-CDR2:DVS(SEQ ID NO:108)

LC-CDR3:CSYAGSYTWV(SEQ ID NO:131)；

Or

LC-CDR1:SSDVGGYNF(SEQ ID NO:294)

LC-CDR2:DVN(SEQ ID NO:291)

LC-CDR3:CSYAGGYTWV(SEQ ID NO:276)；

Or

LC-CDR1:SSDVGGYEY(SEQ ID NO:159)

LC-CDR2:DVT(SEQ ID NO:123)

LC-CDR3:CSYAGSYTWV(SEQ ID NO:131)；

Or

LC-CDR1:SSDVAGYNY(SEQ ID NO:330)

LC-CDR2:DVT(SEQ ID NO:123)

LC-CDR3:CSYAGSYTWV(SEQ ID NO:131)；

Or

LC-CDR1:SSDVGAYNY(SEQ ID NO:110)

LC-CDR2:DVN(SEQ ID NO:291)

LC-CDR3:CSYAGSYTWV(SEQ ID NO:131)；

Or

LC-CDR1:SSDVGAYDY(SEQ ID NO:333)

LC-CDR2:DVT(SEQ ID NO:123)

LC-CDR3:ASYTRSSVWV(SEQ ID NO:334)；

Or

LC-CDR1:SSDVGGYNY(SEQ ID NO:107)

LC-CDR2:DVN(SEQ ID NO:291)

LC-CDR3:CSYAGRYTWM(SEQ ID NO:336)；

Or

LC-CDR1:ISDVGGYNY(SEQ ID NO:122)

LC-CDR2:DVT(SEQ ID NO:123)

LC-CDR3:SSYAGSYTWV(SEQ ID NO:124)；

Or

LC-CDR1:RRDVGGYDF(SEQ ID NO:339)

LC-CDR2:DVS(SEQ ID NO:108)

LC-CDR3:CSYAGTYTWV(SEQ ID NO:340)；

Or

LC-CDR1:SSDVGGYNY(SEQ ID NO:107)

LC-CDR2:DVG(SEQ ID NO:133)

LC-CDR3:CSYAGGYTWV(SEQ ID NO:276)；

Or

LC-CDR1:SSDVGAYNY(SEQ ID NO:110)

LC-CDR2:DVS(SEQ ID NO:108)

LC-CDR3:CSYAGSYTWV(SEQ ID NO:131)；

Or

LC-CDR1:SSDVGTYNY(SEQ ID NO:344)

LC-CDR2:DVS(SEQ ID NO:108)

LC-CDR3:CSYAGFYTWV(SEQ ID NO:345)；

Or

LC-CDR1:SSDIGVYNY(SEQ ID NO:347)

LC-CDR2:DVS(SEQ ID NO:108)

LC-CDR3:CSYAGSYTWV(SEQ ID NO:131)；

Or

LC-CDR1:GSNVGGYNY(SEQ ID NO:349)

LC-CDR2:DVS(SEQ ID NO:108)

LC-CDR3:CSYAGTYTWV(SEQ ID NO:340)；

Or

LC-CDR1:SSDVGGYNY(SEQ ID NO:107)

LC-CDR2:DVT(SEQ ID NO:123)

LC-CDR3:SSYAGSYTWV(SEQ ID NO:124)；

Or

LC-CDR1:SSDVGGYNY(SEQ ID NO:107)

LC-CDR2:DVS(SEQ ID NO:108)

LC-CDR3:SSYTSSSSWV(SEQ ID NO:109)；

Or

LC-CDR1:QAINSY(SEQ ID NO:352)

LC-CDR2:AAS(SEQ ID NO:102)

LC-CDR3:QQSYSTPSWT(SEQ ID NO:354)；

Or

LC-CDR1:QSFSSSY(SEQ ID NO:356)

LC-CDR2:GAS(SEQ ID NO:138)

LC-CDR3:QQSSTSPTWA(SEQ ID NO:357)；

Or

LC-CDR1:QSVNSAY(SEQ ID NO:359)

LC-CDR2:GAS(SEQ ID NO:138)

LC-CDR3:QQSYSDPRWT(SEQ ID NO:360)；

Or

LC-CDR1:QIISSY(SEQ ID NO:155)

LC-CDR2:AAS(SEQ ID NO:102)

LC-CDR3:QQSYSTPTWT(SEQ ID NO:156)；

Or

LC-CDR1:SSDVGGYNY(SEQ ID NO:107)

LC-CDR2:DVN(SEQ ID NO:291

LC-CDR3:NSYTSGSTWV(SEQ ID NO:362)；

Or

LC-CDR1:ISDVGGYNY(SEQ ID NO:122)

LC-CDR2:DVT(SEQ ID NO:123)

LC-CDR3:SSYAGGYTWV(SEQ ID NO:364)；

Or

LC-CDR1:QIISSY(SEQ ID NO:155)

LC-CDR2:AAS(SEQ ID NO:102)；

Or

LC-CDR1:QSVSSSY(SEQ ID NO:367)

LC-CDR2:GAS(SEQ ID NO:138)

LC-CDR3:QQSYSTPTWT(SEQ ID NO:156)。

46. An optionally isolated antibody or antigen-binding fragment capable of binding IL-11 comprising light and heavy chain variable region sequences, wherein:

the light chain includes LC-CDR1, LC-CDR2, LC-CDR3, has at least 85% overall sequence identity to LC-CDR1, LC-CDR1: x₁₃₈X₁₃₉DVGGYX₁₄₀X₁₄₁(SEQ ID NO:393),SSDVX₁₄₂X₁₄₃YX₁₄₄Y(SEQ ID NO:394),X₁₄₅X₁₄₆DX₁₄₇GAYNY(SEQ ID NO:395),SSDIGX₁₄₈YNY(SEQ ID NO:396),X₁₄₉SDVGAYDY(SEQ ID NO:397),SGDVGTYX₁₅₀Y(SEQ ID NO:398),QX₁₅₁IX₁₅₂SY(SEQ ID NO:399),QSX₁₅₃SSSY(SEQ ID NO:400),RX₁₅₄DX₁₅₅GGYDX₁₅₆(SEQ ID NO:401), SSNVGGYNY (SEQ ID NO:284), GSNVGGYNY (SEQ ID NO:349) or QSVNSAY (SEQ ID NO: 359); LC-CDR 2: DVX₁₅₇(SEQ ID NO:402) or X₁₅₈One of AS (SEQ ID NO: 403);LC-CDR3：X₁₅₉SYAGX₁₆₀X₁₆₁X₁₆₂WX₁₆₃(SEQ ID NO:404),SSYTX₁₆₄X₁₆₅X₁₆₆X₁₆₇WV(SEQ ID NO:405),QQSYSX₁₆₈PX₁₆₉WT(SEQ ID NO:406),SSFX₁₇₀X₁₇₁SX₁₇₂X₁₇₃one of WV (SEQ ID NO:407), NSYTSGSTWV (SEQ ID NO:362), ASYTRSSVWV (SEQ ID NO:334), QQSSTSPTWA (SEQ ID NO:357), or SSYRSGSTLGVRRRDQADRPR (SEQ ID NO: 282); and

47. An optionally isolated antibody or antigen-binding fragment capable of binding IL-11 comprising light and heavy chain variable region sequences, wherein:

48. An optionally isolated antibody or antigen-binding fragment capable of binding IL-11 comprising an amino acid sequence having at least 85% sequence identity to the sequence of one of SEQ ID NOs:412 to 475.

49. An optionally isolated antibody or antigen-binding fragment capable of binding IL-11, which is capable of inhibiting IL-11 trans-signaling, optionally wherein the antibody or antigen-binding fragment is the antibody or antigen-binding fragment of any one of claims 37-48.

50. The antibody or antigen-binding fragment of any one of claims 37 to 49, wherein the antibody or antigen-binding fragment is conjugated to a drug moiety or detectable moiety.

51. An optionally isolated in vitro complex comprising the antibody or antigen-binding fragment of any one of claims 37-50 bound to IL-11.

52. A composition comprising the antibody or antigen-binding fragment of any one of claims 37-50, and at least one pharmaceutically acceptable carrier.

53. An isolated nucleic acid encoding the antibody or antigen-binding fragment of any one of claims 37-50.

54. A vector comprising the nucleic acid of claim 53.

55. A host cell comprising the vector of claim 54.

56. A method of making the antibody or antigen-binding fragment of any one of claims 37-50, comprising culturing the host cell of claim 55 under conditions suitable for expression of the antibody or antigen-binding fragment, and recovering the antibody or antigen-binding fragment.

57. An antibody, antigen-binding fragment or composition according to any one of claims 37 to 50 or 52 for use in therapy or in a method of medical treatment.

58. An antibody, antigen-binding fragment or composition according to any one of claims 37 to 50 or 52 for use in the treatment or prevention of fibrosis, or a disease/disorder characterised by fibrosis.

59. An antibody, antigen-binding fragment, or composition of any one of claims 37-50 or 52 for use in treating cancer.

60. Use of an antibody, antigen-binding fragment, or composition of any one of claims 37-50 or 52 in the manufacture of a medicament for treating or preventing fibrosis or a disease/disorder characterized by fibrosis.

61. Use of an antibody, antigen-binding fragment, or composition of any one of claims 37-50 or 52 in the manufacture of a medicament for the treatment or prevention of cancer.

62. A method of treating fibrosis, comprising administering the antibody, antigen-binding fragment, or composition of any one of claims 37-50 or 52 to an individual having fibrosis or a disease/disorder characterized by fibrosis.

63. A method of treating cancer, comprising administering to an individual having cancer the antibody, antigen-binding fragment, or composition of any one of claims 37-50 or 52.

64. A method comprising contacting a sample containing or suspected of containing IL-11 with the antibody or antigen-binding fragment of any one of claims 37-50 and detecting the formation of a complex between the antibody or antigen-binding fragment and IL-11.

65. A method of diagnosing a disease or disorder in an individual, comprising contacting a sample from an individual with the antibody or antigen-binding fragment of any one of claims 37-50 in vitro and detecting the formation of a complex of the antibody or antigen-binding fragment and IL-11.

66. A method of selecting or stratifying an individual for treatment with an IL-11-targeted agent, comprising contacting a sample from an individual in vitro with the antibody or antigen-binding fragment of any one of claims 37-50 and detecting the formation of a complex of the antibody or antigen-binding fragment and IL-11.

67. Use of an antibody or antigen-binding fragment of any one of claims 37-50 to detect IL-11 in vitro or in vivo.

68. Use of an antibody or antigen-binding fragment according to any one of claims 37 to 50 as a diagnostic or prognostic agent in vitro or in vivo.

69. An optionally isolated antibody or antigen-binding fragment capable of binding IL-11 comprising amino acid sequences i) to vi):

ii)LC-CDR2:X₁₈₄AS(SEQ ID NO:569)；

iv)HC-CDR1:GYTFTX₁₈₀YX₁₈₁(SEQ ID NO:567)；

70. The antibody or antigen-binding fragment of claim 69, wherein HC-CDR1 is one of GYTFTDYN (SEQ ID NO:542) or GYTFTSYG (SEQ ID NO: 228).

71. The antibody or antigen-binding fragment of claim 69 or claim 70, wherein HC-CDR2 is one of INPHNGGP (SEQ ID NO: 543), INPDNGGT (SEQ ID NO: 546), INPNNGGI (SEQ ID NO: 549), or IYPRSSNT (SEQ ID NO: 552).

72. The antibody or antigen-binding fragment of any one of claims 69 to 71, wherein HC-CDR3 is one of ARGELGHWYFDV (SEQ ID NO:544), AREGPYGYTWFAY (SEQ ID NO:547), ARNPSLYDGYLDC (SEQ ID NO:550) or ARANWVGYFDV (SEQ ID NO: 553).

73. The antibody or antigen-binding fragment of any one of claims 69 to 72, wherein LC-CDR1 is one of ENVVTY (SEQ ID NO:555), QSIGTS (SEQ ID NO:558), QSLLYNSSQKNY (SEQ ID NO:562), or QDVGTA (SEQ ID NO: 565).

74. The antibody or antigen-binding fragment of any one of claims 69 to 73, wherein the LC-CDR2 is one of GAS (SEQ ID NO:138), YAS (SEQ ID NO: 559) or WAS (SEQ ID NO: 563).

75. The antibody or antigen-binding fragment of any one of claims 69 to 74, wherein LC-CDR3 is one of GQGYSYPYT (SEQ ID NO: 556), QQSNSWPLT (SEQ ID NO: 560), QQYYSYPLT (SEQ ID NO: 563), or QQYSSYRT (SEQ ID NO: 566).

76. The antibody or antigen-binding fragment of any one of claims 69 to 75, wherein the antibody or antigen-binding fragment has at least one heavy chain variable region comprising the following CDRs:

HC-CDR1:GYTFTDYN(SEQ ID NO:542)

HC-CDR2:INPHNGGP(SEQ ID NO:543)

HC-CDR3:ARGELGHWYFDV(SEQ ID NO:544)；

or

HC-CDR1:GYTFTDYN(SEQ ID NO:542)

HC-CDR2:INPDNGGT(SEQ ID NO:546)

HC-CDR3:AREGPYGYTWFAY(SEQ ID NO:547)；

Or

HC-CDR1:GYTFTDYN(SEQ ID NO:542)

HC-CDR2:INPNNGGI(SEQ ID NO:549)

HC-CDR3:ARNPSLYDGYLDC(SEQ ID NO:550)；

Or

HC-CDR1:GYTFTSYG(SEQ ID NO:228)

HC-CDR2:IYPRSSNT(SEQ ID NO:552)

HC-CDR3:ARANWVGYFDV(SEQ ID NO:553)。

77. The antibody or antigen-binding fragment of any one of claims 69 to 76, wherein the antibody or antigen-binding fragment has at least one heavy chain variable region comprising the following CDRs:

LC-CDR1:ENVVTY(SEQ ID NO:555)

LC-CDR2:GAS(SEQ ID NO:138)

LC-CDR3:GQGYSYPYT(SEQ ID NO:556)；

or

LC-CDR1:QSIGTS(SEQ ID NO:558)

LC-CDR2:YAS(SEQ ID NO:559)

LC-CDR3:QQSNSWPLT(SEQ ID NO:560)；

Or

LC-CDR1:QSLLYNSSQKNY(SEQ ID NO:562)

LC-CDR2:WAS(SEQ ID NO:563)

LC-CDR3:QQYYSYPLT(SEQ ID NO:581)；

Or

LC-CDR1:QDVGTA(SEQ ID NO:565)

LC-CDR2:WAS(SEQ ID NO:563)

LC-CDR3:QQYSSYRT(SEQ ID NO:566)。

78. An optionally isolated antibody or antigen-binding fragment capable of binding IL-11 comprising light and heavy chain variable region sequences, wherein:

the heavy chain comprises HC-CDR1, HC-CDR2, HC-CDR3, having at least 8 of the length of HC-CDR15% overall sequence identity, HC-CDR 1: GYTFTX₁₈₀YX₁₈₁(SEQ ID NO:567)；HC-CDR2：INPX₁₈₂NGGX₁₈₃(SEQ ID NO:568) or IYPRSSNT (SEQ ID NO: 552); HC-CDR3: ARGELGHWYFDV (SEQ ID NO:544), AREGPYGYTWFAY (SEQ ID NO:547), ARNPSLYDGYLDC (SEQ ID NO:550) or ARANWVGYFDV (SEQ ID NO: 553);

79. An optionally isolated antibody or antigen-binding fragment capable of binding IL-11 comprising light and heavy chain variable region sequences, wherein:

heavy chain sequences and SEQ ID NOs: 541. the heavy chain sequence of one of 545, 548 or 551 has at least 85% sequence identity.

80. An optionally isolated antibody or antigen-binding fragment capable of binding IL-11, which is capable of inhibiting IL-11 trans-signaling, optionally wherein the antibody or antigen-binding fragment is the antibody or antigen-binding fragment of any one of claims 69-79.

81. The antibody or antigen-binding fragment of any one of claims 69 to 79, wherein the antibody or antigen-binding fragment is conjugated to a drug moiety or a detectable moiety.

82. An optionally isolated in vitro complex comprising the antibody or antigen-binding fragment of any one of claims 69-81 bound to IL-11.

83. A composition comprising the antibody or antigen-binding fragment of any one of claims 69-81, and at least one pharmaceutically acceptable carrier.

84. An isolated nucleic acid encoding the antibody or antigen-binding fragment of any one of claims 69-81.

85. A vector comprising the nucleic acid of claim 84.

86. A host cell comprising the vector of claim 85.

87. A method of making the antibody or antigen-binding fragment of any one of claims 69-81, comprising culturing the host cell of claim 86 under conditions suitable for expression of the antibody or antigen-binding fragment, and recovering the antibody or antigen-binding fragment.

88. An antibody, antigen-binding fragment, or composition of any one of claims 69-81 or 83 for use in a method of therapy or medical treatment.

89. Use of an antibody, antigen-binding fragment, or composition of any one of claims 69-81 or 83 for treating or preventing fibrosis, or a disease/disorder characterized by fibrosis.

90. An antibody, antigen-binding fragment, or composition of any one of claims 69-81 or 83 for use in the treatment of cancer.

91. Use of an antibody, antigen-binding fragment, or composition of any one of claims 69-81 or 83 in the preparation of a medicament for treating or preventing fibrosis or a disease/disorder characterized by fibrosis.

92. Use of the antibody, antigen-binding fragment, or composition of any one of claims 69-81 or 83 in the preparation of a medicament for the treatment or prevention of cancer.

93. A method of treating fibrosis, comprising administering the antibody, antigen-binding fragment, or composition of any of claims 69-81 or 83 to an individual having fibrosis or a disease/disorder characterized by fibrosis.

94. A method of treating cancer, comprising administering to an individual having cancer the antibody, antigen-binding fragment, or composition of any one of claims 69-81 or 83.

95. A method comprising contacting a sample containing or suspected of containing IL-11 with the antibody or antigen-binding fragment of any one of claims 69-81, and detecting the formation of a complex of the antibody or antigen-binding fragment and IL-11.

96. A method of diagnosing a disease or disorder in an individual, comprising contacting a sample from an individual with the antibody or antigen-binding fragment of any one of claims 69-81 in vitro and detecting the formation of a complex of the antibody or antigen-binding fragment and IL-11.

97. A method of selecting or stratifying an individual for treatment with an IL-11 targeting agent, said method comprising contacting a sample from an individual in vitro with the antibody or antigen-binding fragment of any one of claims 69-81 and detecting the formation of a complex of said antibody or antigen-binding fragment and IL-11.

98. Use of an antibody or antigen-binding fragment of any one of claims 69-81 to detect IL-11 in vitro or in vivo.

99. Use of an antibody or antigen-binding fragment of any one of claims 69 to 81 as a diagnostic or prognostic agent in vitro or in vivo.