(19) United States
`(12) Patent Application Publication (10) Pub. No.: US 2014/0219919 A1
`EDWARDS et al.
`(43) Pub. Date:
`Aug. 7, 2014
`
`US 20140219919A1
`
`(54) IL-11 RBINDING PROTEINS AND USES
`THEREOF
`
`(71) Applicant: CSL Limited, Parkville (AU)
`(72) Inventors: Kirsten EDWARDS, Parkville (AU):
`Matthew HARDY, Parkville (AU):
`Veronika RAYZMAN, Parkville (AU):
`Michael WILSON, Parkville (AU)
`
`(73) Assignee: CSL Limited, Parkville (AU)
`
`(21) Appl. No.: 14/174,009
`
`(22) Filed:
`
`Feb. 6, 2014
`
`Related U.S. Application Data
`(60) Provisional application No. 61/764,756, filed on Feb.
`14, 2013.
`
`(30)
`
`Foreign Application Priority Data
`
`Feb. 7, 2013 (AU) ................................ 2O1390O389
`Publication Classification
`
`(2006.01)
`(2006.01)
`(2006.01)
`
`(51) Int. Cl.
`C07K 6/28
`GOIN33/569
`A614.9/00
`52) U.S. C.
`(52) CPC ............. C07K 16/2866 (2013.01); A61K 49/00
`(2013.01); G0IN33/56966 (2013.01)
`USPC ... 424/9.1; 530/389.1:530/387.9; 530/387.3;
`530/391.1:536/23.53; 435/320.1; 435/252.33;
`424/172.1; 435/7.21: 435/254.2:435/334
`ABSTRACT
`(57)
`The present disclosure provides proteins comprising antigen
`binding sites of antibodies that bind to interleukin-11 (IL-11)
`receptor alpha (IL-11 RO) and uses thereof, e.g., in therapy.
`
`Lassen - Exhibit 1008, p. 1
`
`

`

`Patent Application Publication
`
`Aug. 7, 2014 Sheet 1 of 8
`
`US 2014/0219919 Al
`
`SE2 LL XINNYLN
`TS-303
`VIYWVE
`TS-305
`VGIYVE
`YVDRYVE
`TS-306
`VSMYVE
`TS-3a0F7
`VAMYTIE
`TS-316
`bi
`TS-31iL
`TS-312
`TS-313
`TS-322
`Consensus
`
`Vsort
`TGQ
`VaGYV!
`VHEYM
`VSEYVE
`
`5 OT
`
`8E2 L3.2 DNLSPT
`TS-49
`TS-S1
`TS-35
`TS-37
`TS-53
`TS-63
`TS-64
`Consensus
`
`ESQAPE
`ESQWUPEF
`
`ETOTPA
`ETQMEL
`ETQQPF
`DLQOPN
`ESQWES
`ETQXPY
`
`BE2 L3.1 OQYDNE
`
`TS-~2
`OQAEDO
`Ta-4
`QQHEFO
`TS-6
`EQFESO
`TS-7
`QQHENO
`Pg-9
`QQAEEO
`TS-13
`QONETO
`TS-14
`QQHONG
`TS-17
`SQFESO
`TS-20
`QONESO
`TS~-21
`QOSESO
`F822
`QQFETO
`Pg-29
`OOSEEO
`Ts3-32
`POWETO
`Consensus
`QOOXESG
`
`Figure 1
`
`Lassen - Exhibit 1008, p. 2
`
`Lassen - Exhibit 1008, p. 2
`
`

`

`Patent Application Publication
`
`Aug. 7, 2014 Sheet 2 of 8
`
`US 2014/0219919 Al
`
`SE2 H2 VPSGGH
`s-37
`VEWAIY
`TS-1LOL
`YPWGDL
`TS-103
`VPYEDL
`’S-104
`¥VEPWSTI
`TS-Lo?
`VEWGDE
`Ta-Lod
`VPWGTL
`TS-Li5
`VPHGDL
`Consensus VEWGDL
`
`SE2 Hl SWYSNT
`TS-66
`AWWSTA
`TS-69
`SWHsvrT
`TS-71
`WRWSTT
`TS-75
`WRWS LT
`T3-79
`AWPSVT
`T-AG
`WRYSVT
`TS-88
`WERMSTT
`TS-8o
`#RWS IT
`TS-90
`EWYSLT
`TS-31
`SWWSLT
`TS~-S2
`SWWSIT
`Consensus WWWSIT
`
`
`
`Figure 2
`
`BE2 HS.) GPGWGS
`
`be
`
`
`
`Z
`FE
`
`Cousens
` PEDWGK
`
`8E2 83.2 WGSEDL
`
`WOQEAY
`TS-214
`TS-214 WS FW
`TS-215
`Wad FW
`TS-218
`WGSFWE
`TS-221
`WGSEWY
`TS-222
`WOTFAY
`TERA WGSFWt
`consensus WGSEWY
`
`Lassen - Exhibit 1008, p. 3
`
`Lassen - Exhibit 1008, p. 3
`
`

`

`Patent Application Publication
`
`Aug. 7, 2014 Sheet 3 of 8
`
`US 2014/0219919 Al
`
`
`
`CDR2
`|DASNLOT
`DASNLOT
`DASNLOT
`DASNLOT
`DASNLQT
`DASNLOT
`DASNLOT
`DASNLOT
`DASNLOT
`DASNLOQT
`DASNLOQT
`DASNLOT
`DASNLOT
`DASNLOT
`DASNLOT
`DASWLOT
`DASNLOT
`DASNLO?T
`DASNLOT
`DASNLOT
`DASNLOT
`DASNLOT
`DASNLOT
`DASNLOT
`DASNLOT
`DASNLOT
`DASNLOT
`DASNLQT
`DASNLOT
`DASNLOT
`
`DASNLOT
`
`CDRL
`
`DIOMTOSPSSLSASVGDRVTITC) QASOD INNYLN]| WYQOKPGKAPKLLIY
`
`DIQMTQSPSSLSASVGDRVTITC] QASOQD VDYWVE] WYQQKPGRKRAPKLLIY
`DIQMTQSPSSLSASVGDRVTITC] QASOD VGIYVE] WYQQKPGKAPKLLIY¥
`DIQOMTOQSPSSLUSASVGDRVTITC] QASQD VDKYVE] WYQQKPGKAPKLLIY
`DIOMTOSPSSLSASVGDRVTITC] QASQD VSMYVE} WYQOQKPGKAPKLLIY
`DIQMTOSPSSLSASVGDRVIITC) QASOD VAMYIE| WYQOKPGKAPKLLIY
`
`DIOMTOSPSSLSASVGDRVTITC) QASQD VSOQYTE} WYQQKPGKAPKLLIY
`
`DIQMTOSPSSLSASVGDRVTITC! QASGD IGOYVE] WYQQKPGKAPKLLIY
`
`DIQOMTOSPSSLSASVGDRVTITC} QASGD VSGYVE] WYQQKPGKAPKLLIY
`
`DIQMTOSPSSLSASVGDRVTITC] QASQD VHHYME] WYOQKPGKAPKLLIY
`DIQMTQOSPSSLSASVGDRVTITC] QASQD INNYLN} WYQOKPGKAPKLLIY
`
`DIQMTOSPSSLSASVGDRVTITC] QASQD INNYLN}] WYOQKPGKAPKLLIY
`DIQMTOSPSSLSASVGDRVTITC| OASOD
`ENNYUN}| WYQOKPGKAPKLLIY
`
`DIQMTOSPSSLSASVGDRVTITC) GASQD INNYLN] WYQQXPGKAPKLLIY
`DIQOMTOSPSSLSASVGDRVTITC| QASQD INNYLN] WYQQKPGKAPKLLIY
`
`DIOMTOSPSSLSASVGDRVTITC] QASQD INNYLN| WYQQKPGKAPKLLIY
`
`DIQOMTQOSPSSLSASVGDRVTITC] QASQD INNYLN] WYOQKPGKAPKLLIY
`DIOMTOSPSSLSASVGDRVTITC} QASQD
`INNYLN] WYQOKPGKAPKLLIY
`
`DIQMTQSPSSLSASVGDRVTITC} OASQD INNYLN] WYQQKPGKAPKLLIY
`
`DIQMTQSPSSLSASVGDRVTITC] QASQD INNYLN] WYCOKPGKAPKLLIY
`
`DIQMTOSPSSLSASVGDRVTITC] QASQD INNYLN{ WYQQKPGKAPKLLIY
`
`DIOMTOSPSSLSASVGDRVTITIC) QASQD INNYLN}] WYQQKPGKAPKLLIY
`DIOMTOSPSSLSASVGDRVTITC! QASQD INNYLN}] WYQOKPGRKAPKLLIY
`
`DIQMTOSPSSLSASVGORVTITC QASOD
`INNYLN} WYQOKPGKAPKLLIY
`DIQMTOSFSSLSASVGDRVTITC) QASQD INNYLN] WYQQKPGKAPKLLIY
`
`DIQMTQSPSSLSASVGDRVTITC] QASQD INNYLN| WYQOKPGKAPKLIIY
`
`DIQMTOSPSSLSASVGDRVTITC! QASQD INNYLN} WYQQKPGKAPKLLIY
`
`DIQMTOQOSPSSLSASVGORVTITC) QASQD INNYLN}] WYQOKPGKAPRKLLIY
`DIQMTOSPSSLSASVGDRVTITC! GASOD INNYLN} WYOQKPGKAPKLLIY
`
`DIQMTOSPSSLSASVGDRVTITC QASOD
`INNYLN} WYQOKPGKAPKLLIY
`
`
`DIOMTOSPSSLSASVGDRVTITC} QASQD XXXXXX| WYQOKPGKAPKLLIY
`INNYLN
`VDYWVE
`GI
`I
`SKM
`AM
`HQ
`
`GH
`
`Figure 3A
`
`8E2
`TS-393
`TS-305
`TS-306
`TS~307
`TS-310
`TS-311
`TS-312
`TS-313
`TS~322
`TS-2
`TS-4
`TS-6
`TS-7
`TS-93
`TS-13
`TS-14
`TS-17
`TS-20
`TS-21
`TS-22
`TS-29
`TS-32
`TS~49
`Ts-52i
`TS-55
`TS-S7
`TS-58
`TS-63
`TS-64
`
`Consensus
`
`Lassen - Exhibit 1008, p. 4
`
`Lassen - Exhibit 1008, p. 4
`
`

`

`Patent Application Publication
`
`Aug. 7, 2014 Sheet 4 of 8
`
`US 2014/0219919 Al
`
`CDRS
`
`BE2
`TS-303
`TS~305
`TS-306
`TS-307
`TS~310
`TS-312
`TS-312
`TS-313
`TS-322
`Ts-2
`TS-4
`18-6
`ES-7
`Ts-9
`TS8-13
`Ys-14
`TS-17
`TS-26
`TS-24
`TS-22
`TS-29
`Ts-32
`TS-49
`TS-51
`TS-55
`TS-57
`TS-56
`YS-63
`TS-64
`
`Consensus
`
`
`
`GVPSRESGSGSGTDFTFT I SSLQPEDIALYYC| OOYDNL SPT] FGPGTKVDIK
`GVP SRF SGSGSGTDFTFTISSLOPEDIATYYCl QOYDNL SPT] FGPGTKVDIK
`GVP SRE SGSGSGTDFIFTISSLOPEDIATYYC] OOYDNL SPT] FGPGTKVDIK
`GVP SRFSGSGSGTDFIFTISSLOPEDIATYYC| QOYDNL SPT| FGPGTRVDIK
`GVPSRESGSGSGTDPIFTISSLOPEDIATYYC) CQYDNL SPT] FGPGTKVDIK
`GVP SRFSOSGSGTDFTFTISSLOPEDIATYYC| QOYDNL SPT] FGPGTRVDIK
`
`GVPSRESGSGSGIDFTFTISSLOPRDIATYYC| QOYDNL SPT| FGPGTRVDIK
`GVP SRF SGSGSGIDFTFTISSLOPEDIATYYC| CQOYONL SPT] FGPGTKVDIK
`
`GVPSRPSGSGSGIDFIFTISSLQPEDIATYYC| COYDNL SPT] FGPGTKVDIK
`GVP SRF SGSGSGIDFTFTISSLOFEDIATYYC] CQYDNL SPT| FGPGTKVDIK
`GVP SRF SGSGSGTDF TFTISSLOPEDIATYYC] QOAEDQ SPT| FUPGEKVDIK
`GVPSRF SGSGSGTIDFIFTISSLOPEDIATYYC] QQHEFQ SET| FGPGTKVDIK
`GVP SRF SGSGSGIDFTFTISSLOPEDIATYYC| EQFESQ SPT] *#GPGTKVDIK
`GVPSRFSGSGSGIDFTFTISSLOPEDIATYYC] QQHENQ SPT! FGPGTRVDIK
`GVPSRFESGSGSGIDF TETISSLOPEDIATYYC] QQAEEQ SPT! FGPGTKYDIK
`GVP SRF SGSGSSTDFTFTISSLOPEDIATYYC| GQNETO SPT] FGPGTKVDIK
`GVPSRESGSGSGIDFTFTISSLOPEDIATYYC| QQHDNQ SPT| FGPGTKVDIK
`GVP SRF SGSGSGTDFTFTISSLOPEDIATYYC| SQFESQ SPT] FGPGTKVDIK
`GVP SRF SGSGSGTDFTFTISSLOPEDIATYYC| QQNESQ SET| FGPGTRVDIK
`GVPSRFSGSGSGTDFTFTISSLOPEDIATYYC) QQSESQ SPT| FPGPETKVDIK
`GVPSRF SGSCSGTDFTFTISSLOPEDIATYYC| QQFEIQ SFT| FGFGTRVDIK
`GVPSRFSGSGSGIDFTFTISSLOPEDIATYYC) GOSEEQ SPT| FGPGTKVDIK
`GVPSRPSSSGSGTDF TFTISSLOPEDIATYYC| TOWETO SET| FGPGTRVDIK
`GVPSRF SGSGSGIDFTFTISELOPEDLIATYYC] QOYESQ APE| FGPGTKVDIK
`GVPSRFSGSGSGTDFIFTISSLOPEDIATYYC| GOYESQ WEF| FGPGIKVDIK
`GVPSRESGSGSGIDPIFTISSLOPEDIATYYC| OOYETQ TPA| FGPGIKVDIK
`GVPSRF SGSGSGTDFTFTISSLOPEDLATYYC| OOYETO MPL| FGPGIKVDIK
`GVPSRF SGSGSGTDF LIF TISSLOPEDIATYYC| OOYETO OPP] FGPGIKVDIK
`GVPSRFSGSGSGIDFTETISSLOPEDIATYYC| QOYDIO OPN] FGPGIKVDIK
`GYPSRFSGSGSGIDFIFTISSLOPEDIATY YC) QOYESQ WEQ| FEPGTKVDIK
`
`GVPSRFSGSGSGTDPIFTISSLOPREDTATYYC| XOXXXX XPX| FGPGIKVDIK
`| Q ¥DNL $
`[EB AEDQ A EB
`'S HF wF
`iTFES TA
`i;
`NE ML
`'
`sT ON
`fw
`Q
`
`
`
`Figure 3A Continued
`
`5
`SEQ ID NO:
`6
`SEQ ID NO:
`7
`SEQ ID
`NO:
`8
`SEQ ID NO:
`$
`SEQ ID NO:
`i¢
`SEQ ID Wo:
`11
`SEQ ID NO:
`12
`SEQ ID NO:
`13
`SEQ ID NO:
`SEQ ID NO: 14
`SEQ ED NO:
`15
`SEQ ID No: 16
`SEQ ID NO:
`47
`SEQ ID NO: 18
`SEQ ID NO:
`18
`SEQ ID NO: 20
`SEQ ID NO: 21
`SEQ ID NO:
`22
`SEO ID NO:
`SEQ ID NO:
`SEQ ID NO:
`SEQ ID NO;
`SEQ ID NO:
`SEQ ID NO:
`SEQ ID NO:
`SEQ ID NO:
`SEQ ID NO:
`SEQ TD No:
`SEQ ID NO:
`
`SEQ ID NO: 34
`
`
`
`SEQ ID NO:
`
`35
`
`Lassen - Exhibit 1008, p. 5
`
`Lassen - Exhibit 1008, p. 5
`
`

`

`Patent Application Publication
`
`Aug. 7, 2014 Sheet 5 of 8
`
`US 2014/0219919 Al
`
`CcDRIL
`
`PIQMTOSPSSLSASVGDRVTITC /OASOD TNNYLN] WYOQKPGKAPRLITY
`DIGMTOSPSSLSASVGDRVTITC [QASQN VDKYVE] WYQQRPGKAPKLLIY
`DIGMTOSPSSLSASVGDRVTTTC{QASOD INKYLN| WYQOKPSRKRAPKLLIY IDASNLOT
`
`DIQMTOSPSSLSASVGDRVTTTC [QASON INNYLN| WYQOKPGKAPKLLIY |DASNLOT
`
`DIQMTQSPSSLSASVGDRVTITCIOASGE TRNYLM| WYQUKPGKAPKLLIY |DASNLOT
`
`DIQOMTQSPSSLSASVGDRVTITC /QASGD INNYLN] WYQQKPGKAPKLLIY |IDASNLOT
`BIQMTGSPSSLSASVGDRVTITC |QASCL INNYUN] WYCCKPGRAPKLLIY |DASNLOT
`OIQMTOQSPSSLSASVGDRYTITC
`SXXXYRX| WYOQOKPGKAPELLIY
`DASNLQT
`IDK. LN
`VNN VS
`
`
`
`
`
`
`SEQ
`
`ID No:
`
`
`
`BE2
`Ts-306
`TS-2
`Ts-4
`TS-7
`TS-14
`TS~82
`Canseansus
`
`
`
`Consensus
`
`GVPSRFSCSGSGTDFTFTISSUQPEDIATYYC
`GYVP SRFSGSGSGTDFTFTISSLOPEDIATY YC] GQYONL
`
`GYPSREFSGSGSGTDETFTISSLO
`DIAL Y YC} QOARDS
`GVOSRESSSS
`TDOPTFLLSSLOPEDIATY YC) OOHEFC
`
`
`PEPTLSSLOPEDIATY YC) OOHENG
`
`
`“SGSGEGTOPTFTISSLOPEDIATY YC] OORDNG
`
`
`GYPSRFSGSGSGTDFTFTISSLOPELRIATYYC| QOYESG
`QOKKEKYON
`ARG
`RF
`
`BT
`WE
`
`FGPGTKVOTX
`FGPGTRVDIRX
`FGPGTKVDIK
`FGPGTEVDIK
`FGPGTRVDIX
`FGPCGTKVDIX
`FGPGTEVOLTK
`FOPGTKVOTK
`
`SEO
`SEQ
`SEQ
`SEQ
`SEQ
`SEQ
`SES
`
`ID
`ID NO:
`
`
`
`
`
`i6
`16
`18
`at
`23
`w nm
`
`CDRS
`
`
`
`
`
`
`Figure 3B
`
`Lassen - Exhibit 1008, p. 6
`
`Lassen - Exhibit 1008, p. 6
`
`

`

`Patent Application Publication
`
`Aug. 7, 2014 Sheet 6 of 8
`
`US 2014/0219919 Al
`
`
`
`cDRa2
`
`TOVADSVKG
`LOYADSVKG
`TOYADSVKG
`TOYADSVRG
`TOYADSVKG
`TOYADSVKGE
`TOYADSVKG
`TOYADSVAG
`LOYADSVKG
`TOYADSVAG
`TQOYADSVS
`
`TOYADSVAKG
`TOYADSVRS
`TOYADSVKG
`TOYADSVRG
`TOYADS
`
`TOYADSVRG
`TOYADS
`
`TOYADSVR
`TOYADSVKG
`TOYADSVEG
`TOYADSVKG
`TOYADSVEG
`TQOYADSVKG
`TOQOYADSVRG
`TOYADSVES
`TOYADSVKG
`TOYADSVKG
`TOYADSVKG
`TQYADSVRG
`TOYADSVRG
`TOYADSVKG
`TOYADSVEG
`TQOVADSVES
`
`S 3
`
`TOYADSVKG
`
`VPSGCH
`VESGCH
`VPSGGR
`VPSGGH
`VPSGGt
`
`VPSGGH
`VPSGGH
`VPSGGH
`VPSGGH
`VPSGGH
`VPSGGH
`VPWADY
`VPWGEDL
`VPYGDL
`VPWGTI
`VEWGDF
`VPWGTL
`VPHGOL
`VPSGGE
`VPSGGE
`PSCGEH
`VPSGGE
`VPSGGE
`VPSGGH
`VPSGGE
`VPSGGH
`VPSGGE
`VPSGGE
`VPSGGE
`VPSGGE
`VPSGGE
`VPSGGEK
`VPSCGE
`VPSGGE
`VPKKKK
`SGGE
`WADY
`¥ TL
`a
`oT
`F
`
`HRHRAReA
`
`aSeRAHeeeeeer Hw
`
`Lassen - Exhibit 1008, p. 7
`
`
`
`Consensus
`
`
`
`EVOLLESGGGLVQPGGSLRLSCAASGFIF
`
`EVOLLESGGGLVQPGGSLRLSCAASGFIF
`EVOLLESGGGLUVOPGGSLRUSCAASGETE
`
`EVOLLESGGGLVOPGGSURLSCAASGFIF
`EVOLLESGGGLVOPGGSLRLSCAASGFIF
`EVQLLESGGGLVQPGGSLRLSCAASGFIF
`HVOLLESGGGLVOPGGSURLSCAASGFIF
`EVOQLLESGGGLVOPGGSLALSCAASGFTF
`
`EVOLLESGGGLVOPGGSLRALSCAASGFITF
`EVOLLESGGGLVQPGGSLELSCAASGFTIF
`EVJULESGGGLVOPGGSLALSCAASGITF
`EVOLLESGGGLVOPGGSLRLSCAASGFIF
`EVOLLESGGGUVOPGGSLALSCAASGFTF
`QLLESGGGLVOPGGSLRLSCAASGFIF
`BLLESGGGLVQOPGGSLRLSCAASGFIF
`QLLESGGGLVQPGGSLRLSCAASGFTF
`QLLESGGGLVOPGGSLHLSCAASGETF
`VOLLESGGGLVQPGGSLRLSCAASGFIF
`
`QLLESGGEELVOPGGSLALSCAASGFEITF
`ZVOLLESGGGLVQPGGSLELSCAASGFIE
`
`EVOLLESGGGLVOPGGSLRLSCAASGFIF
`
`EVOLLESGGGLVOPGGSLRLSCAASGETE
`
`EVOLLESGGELVOPGGESLRLUSCAASGEIF
`EVOLLESGGELVOPGGSLRLSCAASGFIF
`ZVOLLESGGGLVQPGGSLRLSCAASGFT?
`EVOLLESGGGLVOQPGGSLRUSCAASGF
`
`
`EVQLLESGGGLVOPGGSLELSCAASGET#
`EVOLLESGGGLVQOPGGSLRLSCAASGFT?
`
`EVOLLESGGELVOPGGSLRLSCAASGFIF
`AVOLLESGGGLYQPGGSLRLSCAASGFT?
`BVOQLLESGGELVQOPGGSLRLSCAASGFIIF
`BVOLLESGGELVOPGGSLRLSCAASGF
`
`
`EVOLLESGGGLVOPGGESLRLSCAASG
`EVOLLESGGELVOPGGSLRLSCAASGIIE
`EVOLLESGCCLVOPGGSLRUSCAASGFITF
`
`ur
`
`DUMDTMANHAHMAHAHANHa
`
`WnAhhAw
`ZQRMaON
`
` Wy SMT
`
`
`
`CDR
`WVRCAPGKGLENVS
`
`WWSTA
`WVRCAPGKGLEWVE
`
`WuSVT
`WVRQAPGKGLEWVS
`
`AWS TT
`WVRQAPGKGLEWVS
`
`WS IT
`WVROAPGRGLENVS
`
`NESVT
`WVRQAPGKGLEWVS
`
`WSVT
`WVRQASPGRGLEWNVS
`RYSTT
`
`WVEQAPGKGLEWVS
`RWSTT
`WVRQAPGKGLEWVS
`AWS LT
`WVERQAPGKGLEWVS
`
`MWSIT
`WVRQAPGKGLEWVS
`WY SMT
`
`WVRQAPGKGLEWVS
`AY SMT
`WVRQAPGKGLEWVS
`
`WYSMT
`WVRQAPGKGLEWVS
`WY SMT
`WVRQAPGKGLEWVS
`
`AY SMT
`WVRQAPGKGLEWVS
`MY SMT
`WVRQAPGKGLEWVS
`
`WY SMT
`WVRQAPGKGLEWVS
`ALSMT
`WVRQAPGKGLEWVS
`WY SMT
`WVRQAPGKGLEWVS
`wi sMy
`WVRQAPGKGLEWVS
`WY SMT
`WVRQAPGEGLEWVS
`AY SMT
`WVROAPGKGLERVS
`MYSMT
`WVBR QAPGKGLEWVS
`AYSML
`WV ROQAPGKGLEWVS
`WYSMT
`WVROQAPGKGLEWVS
`AY SMT
`WVYRQAPGKGLEWVS
`WY SMT
`WVROAPGKGLEWVS
`WYSMT
`WVRQAPGKGLEWVS
`WY SsuT
`
`WVRQAPGKGLEWV
`YSMy
`WYRQAPGKGLEWVS
`WY SMT
`
`WVRQAPGKGLEWVS
`YSMT
`WVRQAPGKGUEWVS
`WZSMT
`WVRQAPGKGLEWVS
`XSXX
`fay MT
`
`WVROAPGKGLEWVS
`
`Figure 3C
`
`Lassen - Exhibit 1008, p. 7
`
`

`

`Patent Application Publication
`
`Aug. 7, 2014 Sheet 7 of 8
`
`US 2014/0219919 Al
`
`CDR3
`NO:
`NO:
`NO:
`NO
`NO
`NO?
`WO:
`NO:
`NO:
`Nor
`NO?
`NOs
`NO:
`NO:
`NO:
`TD NO:
`No:
`NC:
`NG:
`No:
`NO:
`NC:
`
`tH
`
`
`
`ID
`ID
`ID
`Id
`ib
`Dh
`Tp
`ID
`
`ID
`
`64
`
`49
`71
`
`AMVDUNRUHDARHOUStGiGlBf2GlldBfbltaLebtileomrcovrooeveMnOcCs
`
`“Ua io m
`
`tHbe
`
`Figure 3C Continued
`
`Lassen - Exhibit 1008, p. 8
`
`AonwRo .| NGRETLVTVSS
`RFT ISRUNSKNTLYLGMNSLRARDTAVYYCAX!
`
`WGRGTLVTVSS
`WGRGTLVIVES
`WGRGTLVIVSS
`WGRGTLVTVSS
`WGRGTLVIVSS
`WGRGTLVIVSS
`WGRGTLVIVSS
`WGORGILVIVSS
`WGRGTLYTVS8
`WGRGTLVIVSS
`WGRGTLVIVSS
`WGRGTLVEVS
` WGRGTLVIVSS
`WGRGTLVTVSS
`
`WGRGTL
`
`WGRGTLY
`bE
`
`WGRGTLVIV
`WGRGTL
`
`WSRGTL
`WGRETL
`WGRGTLV
`
`WGRGTL
`WGRGTLY
`WGRGTL
`WGRGTLVT
`WGRGTLVIV
`
`WGRGTLY
`WGRGTLVT
`
`WGR2GTL
`WGRGTLYIVS3
`
`WGRGTLYTVSS
`
`WGSFDL
`
`WGEEDL
`WGSFDL
`WGSFDL
`WGSFDL
`WOSFDL
`WGSFDL
`WOSEDL
`WOSFDL
`WGSFRL
`WGSFUL
`WGSFDL
`WGOSFOL
`WGSFRL
`WGSFDL
`WESFDL
`WESEDL
`WGOMFEL
`WORPDL
`
`WOLFDL
`WOLFOL
`WGRPDL
`WOUFHT
`WOLFEL
`WGORFDL
`WGSFBL
`WGQFAV
`WGBFRE
`WGSFWO
`WOSFWE
`WGSFWY
`WOYEAY
`
`WOSEWT
`WGRERR
`BL
`AV
`WE
`
`aEv¢
`
`RFTISRONSKENTLYLOMNSLRAEDTAVYYCAK|
`RETISRONSKNTLYLOMNSLRAE DIAVYYCAK
`EFTISRONSKNTLYLOMNSLEA
`
`RFTISRONSKNTLYLOMNSLRAEDTAVYYCAK
`RFTISRDNSENTLYLOMNSLRAEDTAVYYCAK
`RETISRONSKNTLYLOMNSLRAEDTAVYYCAK
`RETTSRDNSRNTLYLOMNSLRARDTAVYYCAR
`RFITISRDNSKNTLYLOMNSLAARRTAVY YCAK|
`RETISRDNSENTLYLOMNSLRAEDTAVYYCAK
`RETISRDONSANTLYLOMNSLRAEDTAVYYCAK
`
`NSLRAELTAVYYCAR!
`RFTISRONSANTLYLQMNSLRAREDTAVYYCAR
`RFTISRONSENTLYL OMNSLRABDTAVYYCAK
`RETISRONSENTLYLCMNSLRABDTAVYYCARK|
`RFTISRONSHNTLYLOMNSLRAEDTAVYYCAKI
`RIT ISRONSANTLYLOMNSLRAEDTAVYYCAE
`RETISRONSKNTLYLOMNSLAABDLAVYYCARKI
`RETISRONSKNTLYLCMNSLRARDTAVYYCAY
`RETISRONSKNTLYLOMNSLRAEDTAVYYCAK
`
`RPT ISRDNSENTLYLOMNSLRARDTAVYYCAX
`ARETIERDNSKNTLYLOMNSLRAEDTAVYYCAR
`
`RETISRONSKNTILYLOMNSLRAEDIAVYYCARX
`RETISRONSKNTLYLGMNSLRABRDTAVYYCAZ!
`RET ISRONSKENTLYLOMNSLRAEDTAVYYC
`REPL SRONSKNTLYLOMNSLRAEDTAVYYCA
`
`RFEFTISRONSKNTD YY
`SURAEDLAVYYCAR
`
`RETISRONSKNTLYLOMNSLRARDTAVYYCAX
`
`RETISRONSKNTLYLOMNSLRARDTAVY
`RETISRONSKENTLYLOMNSLRAARDTAVY)
`{|
`
`
`REVISRONSKNTILYLOMNSLRAEDTAVYYCAR
`
`RFT USRONSKNTLYLOMNSLAAEDTAVYYCAX
`
`RFTISRONSKNTLYLOMNSLRSEDTAVYYCAK
`
`RETISRDNSKNTLIYLOMNSLRABRDTAVYYCA
`RFTISRONSKNTLYLOMNSLRAEDTAVYYCAXK
`
`GPS
`GEG
`GPG
`GPS
`GPG
`GPG
`GPG GPG
`GPG
`GPG
`GPG
`GPG
`GPG
`CPG
`GPG
`GPG
`GP
`FED
`PVD
`PED
`PLD
`PLD
`PND
`PRD
`PRD
`PED
`GPG
`GEG
`GEG
`GEG
`GPG
`GPG
`GPG
`KKK
`GPE
`PED
`
` 140
`
`6-143
`
`TS-152
`TS~-156
`Ts~213
`rs-214
`TS-215
`TS-218
`TS-222
`TS-222
`Ts-224
`Consensus
`
`Lassen - Exhibit 1008, p. 8
`
`

`

`Patent Application Publication
`
`Aug. 7, 2014 Sheet 8 of 8
`
`US 2014/0219919 Al
`
`BAZ
`TS-101
`TS-108
`TS-134
`TS-136
`Consensus
`
`SE2
`
`
`
`
`SEG ID NO: 27
`RF TISRDNSKNTLYLOMNSLRARDTAVYYCAK GPG WGSFDLI WGRGTLVTVSS
`
`RETISRDNSKNTLYLOMNSLRAEDTAVYYCAK] GPG WGSFDL] WGRGTLVTV
`RQ TD NO;
`49
`
`
`SEQ ID NO:
`53
`RF TISRDNSKNTLYLOMNSLRAEBDIAVYYCAR] GPS WOSFDL| WGRGTLVIVSS
`SRQ ID NO:
`57
`RF TISRDNSKNTLYLOMNS LRAKDTAVYYCAR] PED WGLFDL| WGRGTLVIVSS
`SEQ ID NO:
`$9
`REVLSA DNSKNTLYLOMNSLRAEDIAVYYCAK] PLD WGREDL| WGRGTLVIVSS
`
`SEQ ID NO:
`72
`Consensus
`RFTISRDNSKNTLYLOMNSLARAEDTAVYYCAK] XXX WGXFOL| WGRGTLVIVSS
`GPG=S
`
`PED
`ob
`L
`R
`
`
`
`
`
`
`
`CORT
`
`EVOLLESGGGLVOPGGSLRUSCAASGFTS § NYSMT JWVROAPGKGLEWVS
`
`EVOLLESGGGLVGPGGSLRLSCAASG
`WXLSMT JWVROADGKGLEWVS
`S
`EVOLLESGGGLVOPGGSLRLSCAAEG!
`JAYSMT [WVRQADPGKGLEWVS
`
`EVOLLESGGGIVOQPGGSLRUSCAASGFTF S MYSMT |WVROAPGKGLEWVS
`EVQLLESGGGLVQPGGSLRLSCAASGFTF
`5S
`PIYSMT |WVROAPGKGLEWVS
`EVOLLESCGCLYQPGGSLRLSCAASGFTF 8 WYSMT |WVROAPGKGLSWVS
`
`CDRZ
`
`VPSGGH TOYADSVKE
`BY VPWGDL TOYADSVKGE
`VPWGTL TQYADSVRE
`VYPSGGH TOYADSVKG
`VESGGH TOYADSVKG
`EI VPXGXX TOYADSVKG
`S Gd
`W DL
`
`BI
`
`L
`
`
`
`Figure 3D
`
`Lassen - Exhibit 1008, p. 9
`
`Lassen - Exhibit 1008, p. 9
`
`

`

`US 2014/02199 19 A1
`
`Aug. 7, 2014
`
`IL-11 RBINDING PROTEINS AND USES
`THEREOF
`
`RELATED APPLICATION DATA
`0001. The present application claims priority from Aus
`tralian Patent Application No. 2013900389 entitled “IL-11R
`binding proteins and uses thereof filed on 7 Feb. 2013 and
`from U.S. Patent Application No. 61/764,756 entitled “IL
`11 Rbinding proteins and uses thereof filed on 14 Feb. 2013.
`The entire contents of those applications are hereby incorpo
`rated by reference.
`
`SEQUENCE LISTING
`0002 The Sequence Listing in the ASCII text file, named
`as P29799 SequenceListingProvisional.txt of 164 KB, cre
`ated on Feb. 14, 2013, and submitted to the United States
`Patent and Trademark Office via EFS-Web, is incorporated
`herein by reference.
`
`FIELD
`0003. The present disclosure relates to proteins compris
`ing antigen binding sites of antibodies that bind to interleu
`kin-11 (IL-11) receptor alpha (IL-11 RC.) and uses thereof,
`e.g., in therapy.
`
`BACKGROUND
`0004 IL-11 is a member of the IL-6 cytokine family which
`also comprises IL-27, IL-31, leukemia inhibitory factor
`(LIF), oncostatin M (OSM) and ciliary neurotrophic factor
`(CNTF) amongst others. IL-6 family cytokines induce signal
`transduction via a common signal-transducing receptor
`B-subunit, gp130 and a specific receptor C-Subunit. In the
`case of IL-11, binding of this cytokine to its specific receptor
`C.-subunit, IL-11 RC, induces gp130 homodimerization.
`Dimerization of gp130 activates the JAK/STAT signaling
`pathway and leads to the activation of signal transducer and
`activator of transcription (STAT) 3 (STAT3) and to a lesser
`extent, STAT1.
`0005 IL-11 signaling is known to play a role in hemato
`poiesis, immune response, inflammation, adipogenesis,
`osteoclastogenesis, neurogenesis, megakaryocyte maturation
`and platelet production. IL-11 is used clinically or is in devel
`opment for treating a variety of conditions, e.g., chemo
`therapy-induced thrombocytopenia, and various inflamma
`tory disorders including arthritis, inflammatory bowel
`disease, radiation-induced lung damage, sepsis and psoriasis.
`However, clinical use of IL-11 has been restricted due to
`reports of serious adverse events including edema. Moreover,
`IL-11 has been shown to have deleterious effects in various
`conditions.
`0006 For example, IL-11 has been found to act as an
`inhibitor of bone formation, and is critical for osteoclast
`formation and activity and bone resorption. Thus, blocking
`the activity of IL-11 has been proposed as a treatment for
`osteoporosis and for preventing bone resorption/promoting
`bone formation in other conditions such as metastatic bone
`cancer, myeloma, Paget’s disease of bone, and bone fracture
`and healing.
`0007 IL-11 signaling has been implicated as having a
`pathogenic role during the early phase of tuberculosis. Block
`ing IL-11 with an anti-IL-11 antibody was shown to diminish
`histopathology and neutrophilic infiltration of the lung tissue
`in mice infected with Mycobacterium tuberculosis.
`
`0008 Antagonism of IL-11 has also been proposed as a
`method of treating Th2-mediated disorders including asthma,
`chronic obstructive pulmonary disease (COPD), rhinitis,
`allergies and atopic dermatitis. In this regard, blocking IL-11
`signaling using a mutant form of IL-11 that does not induce
`signal transduction was shown to be of therapeutic benefit in
`a mouse model of asthma.
`0009 IL-11 and/or IL-11 RC. is overexpressed in liver can
`cer, pancreatic cancer, gastric cancer, osteosarcoma, endome
`trial cancer and ovarian cancer. Moreover, as discussed
`above, IL-11 induced gp130 dimerization leads to activation
`of STAT3, which induces expression of genes associated with
`angiogenesis (e.g. VEGF), cell cycle progression (e.g. cylin
`D1) and cell survival (e.g. Bcl-XL, survival). Persistent
`STAT3 activity appears to be associated with hematologic
`malignancies and tumors of epithelial origin. Excessive
`STAT3 activation promotes the growth and survival of gastric
`cells, is associated with increased gastric angiogenesis and
`leads to gastric tumorigenesis in mice. However, gastric
`inflammation, hyperplasia and tumor formation are Sup
`pressed in IL-11 unresponsive mice or in mice treated with a
`non-signaling mutant of IL-11.
`0010 IL-11 is also involved in other biological processes,
`Such as, inhibition of adipogenesis, induction of cachexia
`(e.g., cancer cachexia), induction of a febrile response, modu
`lation of extracellular matrix metabolism, stimulation of
`acute-phase reactants and embryo implantation.
`0011. It will be apparent to the skilled artisan from the
`foregoing that reagents that neutralize IL-11 signaling are
`desirable for their potential to provide a therapeutic benefit in
`any of a number of diverse conditions. Reagents that bind to
`the IL-11 RC. are also desirable since they have the advantage
`of being capable of specifically targeting cells in vivo as
`opposed to needing to bind to and neutralize soluble IL-11
`throughout a subject.
`0012 Despite this desirability, many reagents (e.g., anti
`bodies) that bind to IL-11 RC. do not neutralize IL-11 signal
`ing. For example, Blanc et al (Journal of Immunological
`Methods 241: 43-59, 2000) described a panel of 14 mouse
`monoclonal antibodies raised against human IL-11 RC, but
`none of them were capable of inhibiting IL-11-induced pro
`liferation of BaF3/gp130/IL-11R cells, indicating that the
`antibodies do not neutralize IL-11 signaling. Commercially
`available anti-IL-11 RC. antibodies, e.g., 4D12 available from
`Santa Cruz, Biotechnology, Inc., also do not neutralize IL-11
`signaling.
`
`SUMMARY
`0013. In producing the present invention, the inventors
`sought to produce reagents (e.g., antibodies and proteins
`comprising antigen binding domains thereof) that bind to
`IL-11 RC. and neutralize IL-11 signaling. The inventors pro
`duced a series of antibodies having Such activity, some of
`which potently neutralize IL-11 signaling, e.g., prevent pro
`liferation of IL-11-dependent BaF3 cell proliferation. These
`antibodies were shown to be cross-reactive with human
`IL-11RC. (hIL-11RC.) and cynomolgus monkey IL-11 RC. (cy
`noIL-11 RO), meaning that they may be used in primate mod
`els of human disease. The antibodies were also found to bind
`to overlapping epitopes. The inventors then affinity matured
`one of these antibodies and produced a series of additional
`antibodies having additional desirable properties, e.g., neu
`tralization of IL-11 signaling and/or improved affinity and/or
`
`Lassen - Exhibit 1008, p. 10
`
`

`

`US 2014/02199 19 A1
`
`Aug. 7, 2014
`
`sequences similar to human germline (e.g., having a reduced
`likelihood of inducing an immune response when adminis
`tered to a human).
`0014 Based on the foregoing, it will be apparent to the
`skilled artisan that the inventors have produced a protein
`comprising an antigen binding domain of an antibody, the
`antigen binding domain capable of binding to or specifically
`binding to IL-11RC. and neutralizing IL-11 signaling.
`0015. In one example, the present disclosure provides an
`IL-11RC.-binding protein comprising an antigen binding
`domain of an antibody, the antigenbinding domain binds to or
`specifically binds to IL-11 RC. and neutralizes IL-11 signal
`ing, wherein the antigenbinding domain is capable of binding
`to hiL-11RC. and cynoIL-11 RC.
`0016. In one example, the IL-11 RC-binding protein neu
`tralizes human IL-11 (hIL-11) and/or cynomolgus monkey
`IL-11 (cynoL-11) signaling.
`0017. The present disclosure additionally or alternatively
`provides an IL-11 RC.-binding protein comprising an antigen
`binding domain of an antibody, wherein the antigen binding
`domain binds to or specifically binds to IL-11 RC. and neu
`tralizes IL-11 signaling and the protein inhibits IL-11 (e.g.,
`hIL-11 or cynolL-11)-mediated proliferation of BaF3 cells
`expressing IL-11 RC. and gp130 with an ICso of 10 ug/ml or
`less. In one example, the ICso is 5ug/ml or less. For example,
`the ICs is 4 g/ml or less or 3.5 g/ml or less. In one example,
`the ICso is 3 ug/ml or less or 2 ug/ml or less. For example, the
`ICs is 1 g/ml or less. For example, the ICs is 0.9 g/ml or
`less or 0.8 g/ml or less or 0.7 g/ml. In one example, the ICso
`is 0.7 ug/ml or less. In one example, relating to each of the
`foregoing examples, the ICso can be 10 pg/ml or more or 10
`ng/ml or more.
`0018. In one example, the IL-11 RC-binding protein inhib
`its IL-11 (e.g., hIL-11 or cynolL-11)-mediated proliferation
`of BaF3 cells expressing IL-11 RC. and gp130 with an ICso at
`least about 1.5 fold greater than antibody 8E2 (comprising a
`heavy chain comprising a sequence set forth in SEQID NO:
`83 and a light chain comprising a sequence set forth in SEQ
`ID NO: 84). In one example, the ICs is at least about 2 fold
`greater or at least about 2.5 fold greater or at least about 3 fold
`greater than antibody 8E2.
`0019. In one example, the ICso is determined by culturing
`BaF3 cells expressing IL-11RC. and gp130(e.g., genetically
`modified to express IL-11 RC. and/or gp130) (e.g., about
`1x10" cells) in the presence of from about 0.5 ng/mL hIL-11
`to about 5 ng/mL hIL-11 (e.g., in the presence of about 0.5
`ng/mL hIL-11 or about 5 ng/mL hIL-11) for about 48 hours.
`In one example, proliferation is determined by measuring
`incorporation of 3H-thymidine into DNA during the last 6
`hours of culture. In assays performed to determine neutral
`ization of cynolL-11, the cells can be cultured in the presence
`offrom about 0.5 ng/mL cynoIL-11 to about 5 ng/mL cynoL
`11 (e.g., in the presence of about 0.5 ng/mL cynoL-11 or
`about 5 ng/mL cynoIL-11).
`0020. The present disclosure additionally or alternatively
`provides an IL-11 RC.-binding protein comprising an antigen
`binding domain of an antibody, wherein the antigen binding
`domain binds to or specifically binds to IL-11 RC. and neu
`tralizes IL-11 signaling and the level of binding of the
`IL-11RC.-binding protein to a polypeptide of SEQID NO: 86
`is lower than the level of binding of the IL-11 RC-binding to a
`polypeptide of SEQID NO:3 and/or 85.
`0021. The present disclosure additionally or alternatively
`provides an IL-11 RC.-binding protein comprising an antigen
`
`binding domain of an antibody, wherein the antigen binding
`domain binds to or specifically binds to IL-11 RC. and neu
`tralizes IL-11 signaling and the level of binding of the
`IL-11RC.-binding protein to a polypeptide of SEQID NO: 89
`is lower than the level of binding of the IL-11 RC-binding to a
`polypeptide of SEQID NO:3 and/or 85.
`0022. In one example, the level of binding is determined
`by Western Blotting and/or by fluorescence-activated cell
`sorting (FACS) of cells expressing the polypeptide.
`0023. In one example, the level of binding of the IL-11 RC.-
`binding protein to the polypeptide of SEQID NO: 86 or 89 is
`reduced by at least about 10 fold or 20 fold or 50 fold or 100
`fold or 150 fold or 200 fold compared to the binding of the
`IL-11RC.-binding protein to the polypeptide of SEQID NO:
`3 and/or 85.
`0024. In one example, the IL-11RC.-binding protein does
`not detectably bind to the polypeptide of SEQID NO: 86 or
`89.
`0025. In one example, the IL-11RC.-binding protein binds
`to a polypeptide of SEQID NO: 87 or 88. For example, the
`level of binding of the IL-11 RC.-binding protein binds to a
`polypeptide of SEQID NO: 87 or 88 is similar to or about the
`same as (e.g., within about 20% or 15% or 10% or 5%) of the
`level of binding to the polypeptide of SEQID NO: 3 and/or
`85.
`0026. The present disclosure additionally or alternatively
`provides an IL-11 RC-binding protein comprising an antigen
`binding domain of an antibody, wherein the antigen binding
`domain binds to or specifically binds to IL-11 RC, and neu
`tralizes IL-11 signaling and the antigenbinding domain binds
`to an epitope comprising residues within the first fibronectin
`III domain of IL-11 RC.
`0027. In one example, the epitope comprises residues
`within the immunoglobulin-like domain and the first
`fibronectin III domain of IL-11RC.
`0028. In one example, the epitope comprises residues
`between amino acids 111-215 of SEQID NO: 1.
`0029. In one example, the epitope comprises residues
`between amino acids 1-215 of SEQID NO: 1.
`0030 The present disclosure additionally or alternatively
`provides an IL-11 RC-binding protein comprising an antigen
`binding domain of an antibody, wherein the antigen binding
`domain binds to or specifically binds to IL-11 RC. and neu
`tralizes IL-11 signaling and wherein the protein competi
`tively inhibits binding of antibody 8E2 (comprising a V
`comprising a sequence set forth in SEQID NO:37 and a V,
`comprising a sequence set forth in SEQ ID NO: 5) to hiL
`11RC. and/or to a polypeptide of SEQID NO:3 and/or 85.
`0031. The present disclosure additionally or alternatively
`provides an IL-11 RC-binding protein comprising an antigen
`binding domain of an antibody, wherein the antigen binding
`domain binds to or specifically binds to IL-11 RC. and neu
`tralizes IL-11 signaling and wherein the protein competi
`tively inhibits binding of antibody 8E4 (comprising a V
`comprising a sequence set forth in SEQID NO: 74 and a V,
`comprising a sequence set forth in SEQID NO: 73) to hiL
`11RC. and/or to a polypeptide of SEQID NO:3 and/or 85.
`0032. The present disclosure additionally or alternatively
`provides an IL-11 RC-binding protein comprising an antigen
`binding domain of an antibody, wherein the antigen binding
`domain binds to or specifically binds to IL-11 RC. and neu
`tralizes IL-11 signaling and wherein the protein competi
`tively inhibits binding of antibody 8D10 (comprising a V
`comprising a sequence set forth in SEQID NO: 76 and a V,
`
`Lassen - Exhibit 1008, p. 11
`
`

`

`US 2014/02199 19 A1
`
`Aug. 7, 2014
`
`comprising a sequence set forth in SEQID NO: 75) to hIL
`11 RC. and/or to a polypeptide of SEQID NO:3 and/or 85.
`0033. The present disclosure additionally or alternatively
`provides an IL-11 RC.-binding protein comprising an antigen
`binding domain of an antibody, wherein the antigen binding
`domain binds to or specifically binds to IL-11 RC. and neu
`tralizes IL-11 signaling and wherein the protein competi
`tively inhibits binding of antibody 8E2 (comprising a heavy
`chain comprising a V comprising a sequence set forth in
`SEQID NO:37 and a human IgG4 constant region and a light
`chain comprising a V, comprising a sequence set forth in
`SEQ ID NO: 5 and a human light chain constant region) to
`hIL-11 RC. and/or to a polypeptide of SEQID NO: 3 and/or
`85.
`0034. The present disclosure additionally or alternatively
`provides an IL-11 RC.-binding protein comprising an antigen
`binding domain of an antibody, wherein the antigen binding
`domain binds to or specifically binds to IL-11 RC. and neu
`tralizes IL-11 signaling and wherein the protein competi
`tively inhibits binding of antibody 8E4 (comprising a heavy
`chain comprising a V comprising a sequence set forth in
`SEQID NO: 74 and a human IgG4 constant region and a light
`chain comprising a V comprising a sequence set forth in
`SEQID NO: 73 and a human light chain constant region) to
`hIL-11 RC. and/or to a polypeptide of SEQID NO: 3 and/or
`85.
`0035. The present disclosure additionally or alternatively
`provides an IL-11 RC.-binding protein comprising an antigen
`binding domain of an antibody, wherein the antigen binding
`domain binds to or specifically binds to IL-11 RC. and neu
`tralizes IL-11 signaling and wherein the protein competi
`tively inhibits binding of antibody 8D10 (comprising a heavy
`chain comprising a V comprising a sequence set forth in
`SEQID NO: 76 and a human IgG4 constant region and a light
`chain comprising a V comprising a sequence set forth in
`SEQID NO: 75 and a human light chain constant region) to
`hIL-11 RC. and/or to a polypeptide of SEQID NO: 3 and/or
`85.
`0036. The present disclosure additionally or alternatively
`provides an IL-11 RC.-binding protein comprising an antigen
`binding domain of an antibody, wherein the antigen binding
`domain binds to or specifically binds to IL-11 RC. and neu
`tralizes IL-11 signaling and wherein the protein competi
`tively inhibits binding of antibody 8E2 (comprising a heavy
`chain comprising a sequence set forth in SEQID NO: 83 and
`a light chain comprising a sequence set forth in SEQID NO:
`84) to hiL-11RC. and/or to a polypeptide of SEQ ID NO: 3
`and/or 85.
`0037. The present disclosure additionally or alternatively
`provides an IL-11 RC.-binding protein comprising an antigen
`binding domain of an antibody, wherein the antigen binding
`domain binds to or specifically binds to IL-11 RC. and neu
`tralizes IL-11 signaling and wherein the protein competi
`tively inhibits binding of antibody 8E4 (comprising a heavy
`chain comprising a sequence set forth in SEQID NO: 92 and
`a light chain comprising a sequence set forth in SEQID NO:
`91) to hiL-11RC. and/or to a polypeptide of SEQ ID NO: 3
`and/or 85.
`0038. The present disclosure additionally or alternatively
`provides an IL-11 RC.-binding protein comprising an antigen
`binding domain of an antibody, wherein the antigen binding
`domain binds to or specifically binds to IL-11 RC. and neu
`tralizes IL-11 signaling and wherein the protein competi
`tively inhibits binding of antibody 8D10 (comprising a
`
`heavy chain comprising a sequence set forth in SEQID NO:
`94 and a light chain comprising a sequence set forth i