US 20180186872A1
`
`(ΐ9) United States
`(ΐ2) Patent Application Publication (ΐο) Pub. No.: US 2018/0186872 Al
`Jul. 5,2018
`Cook et al.
`(43) Pub. Date:
`
`US 20180186872Α1
`
`(54) IL-11RA ANTIBODIES
`
`(30)
`
`Foreign Application Priority Data
`
`(71) Applicants:Singapore Health Services PTE LTD.,
`Singapore (SG); National University of
`Singapore, Singapore (SG)
`
`(72)
`
`Inventors: Stuart Alexander Cook, Singapore
`(SG); Sebastian Schaefer, Singapore
`(SG)
`
`(73) Assignees: Singapore Health Services PTE LTD.,
`Singapore (SG); National University of
`Singapore, Singapore (SG)
`
`(21) Appl. No.: 15/843,212
`
`(22) Filed:
`
`Dec. 15, 2017
`
`Dec. 16, 2016 (GB) .................................... 1621439.7
`Publication Classification
`
`(51)
`
`(2006.01)
`(2006.01)
`(2006.01)
`(2006.01)
`
`Int. Cl.
`C07K16/24
`C07K14/54
`Α61Ρ 35/00
`G01N 33/68
`(52) U.S. Cl.
`CPC ........ C07K 16/244 (2013.01); C07K14/5431
`(2013.01); G01N33/6854 (2013.01); G01N
`33/6869 (2013.01); Α61Ρ 35/00 (2018.01)
`ABSTRACT
`(57)
`IL-llRa antibodies are disclosed. Also disclosed are com
`positions comprising the IL-llRa antibodies, and methods
`using the IL-llRa antibodies.
`
`Lassen - Exhibit 1011, p. 1
`
`
`
`(ΐ9) United States
`(ΐ2) Patent Application Publication (ΐο) Pub. No.: US 2018/0186872 Al
`Jul. 5,2018
`Cook et al.
`(43) Pub. Date:
`
`US 20180186872Α1
`
`(54) IL-11RA ANTIBODIES
`
`(30)
`
`Foreign Application Priority Data
`
`(71) Applicants:Singapore Health Services PTE LTD.,
`Singapore (SG); National University of
`Singapore, Singapore (SG)
`
`(72)
`
`Inventors: Stuart Alexander Cook, Singapore
`(SG); Sebastian Schaefer, Singapore
`(SG)
`
`(73) Assignees: Singapore Health Services PTE LTD.,
`Singapore (SG); National University of
`Singapore, Singapore (SG)
`
`(21) Appl. No.: 15/843,212
`
`(22) Filed:
`
`Dec. 15, 2017
`
`Dec. 16, 2016 (GB) .................................... 1621439.7
`Publication Classification
`
`(51)
`
`(2006.01)
`(2006.01)
`(2006.01)
`(2006.01)
`
`Int. Cl.
`C07K16/24
`C07K14/54
`Α61Ρ 35/00
`G01N 33/68
`(52) U.S. Cl.
`CPC ........ C07K 16/244 (2013.01); C07K14/5431
`(2013.01); G01N33/6854 (2013.01); G01N
`33/6869 (2013.01); Α61Ρ 35/00 (2018.01)
`ABSTRACT
`(57)
`IL-llRa antibodies are disclosed. Also disclosed are com
`positions comprising the IL-llRa antibodies, and methods
`using the IL-llRa antibodies.
`
`Lassen - Exhibit 1011, p. 1
`
`
`
`Patent Application Publication Jul. 5, 2018 Sheet 1 of 61 US 2018/0186872 Α1
`
`240 -
`
`220
`
`200
`180
`
`s Total Reads
`^mapped
`■ unique
`
`pmmm * cosi
`
`w*.
`
`T
`
`***
`
`~
`
`Μ Μ Μ
`
`Mriyni
`
`Primary
`fibr-obbsts
`
`FIG. 2Α
`
`Lassen - Exhibit 1011, p. 2
`
`
`
`Patent Application Publication Jul. 5, 2018 Sheet 2 of 61 US 2018/0186872 Α1
`
`mrm
`
`Atrium
`
`Primary
`Fibroblasts
`
`FIG. 2Β
`
`ΤΝΝΤ2
`
`Atrium
`
`Primary
`Fibroblasts
`
`FIG. 2C
`
`fpm
`
`sss
`
`inο
`
`ο
`
`H D k y
`
`Lassen - Exhibit 1011, p. 3
`
`
`
`Patent Application Publication Jul. 5, 2018 Sheet 3 of 61
`
`US 2018/0186872 Α1
`
`COL1A2
`
`m
`
`FPKM ο
`
`ο
`
`------------ 1------------
`
`Primary
`Fibroblasts
`
`Atriysn
`
`FIG. 2D
`
`mtm
`
`&■m
`
`ο
`§1 H
`
`ο
`m
`
`γ
`
`ψ
`
`€»
`ο¾
`FPKf#
`
`ο
`O
`ο
`
`••O
`
`Atrium
`
`FIG. 2Ε
`
`................i...............
`Primary
`Fibroblasts
`
`ψ
`
`ο
`
`ψ
`
`Lassen - Exhibit 1011, p. 4
`
`
`
`Patent Application Publication Jul. 5, 2018 Sheet 4 of 61
`
`US 2018/0186872 Α1
`
`Upregulated in Fibrosis
`
`Si.11
`FOR- 1,3jdG
`
`Downregulated in Fibrosis
`
`FIG. 3Α
`
`Fold change: 105
`
`TGFB1 —
`
`4·
`
`FIG. 3Β
`
`DEseq2 corrected Fold Change
`
`Lassen - Exhibit 1011, p. 5
`
`
`
`Patent Application Publication
`
`Jul. 5, 2018 Sheet 5 of 61
`
`US 2018/0186872 Α1
`
`TGFB1 -
`
`24h
`
`FIG. 3C
`
`Lassen - Exhibit 1011, p. 6
`
`
`
`Patent Application Publication Jul. 5, 2018 Sheet 6 of 61
`
`US 2018/0186872 Α1
`
`Utah
`
`Ovary BSaSder
`luag Kidney Pituitary Pancreas Stomach Color* Spleen Falfopiart Breast Cervix
`
`Tu&e
`
`Adrenal
`
`Tissue Nerve Heart Esophagus Thyroki Uterus Vagina Gteto Prostate Uvsr
`Brain
`touscie Btood
`Testis
`
`FIG. 3D
`
`Vessel
`
`Adipose
`
`Skin
`
`"throb lasts
`
`Atrsaf
`
`Sioort
`
`O
`
`Τΐ3Ρ·4¾
`
`m
`
`ID
`tadd)
`UO!$$0idX3 U1I
`
`CM
`
`jrsf ·ρ
`
`•f
`
`οο
`
`urs
`CM
`
`Lassen - Exhibit 1011, p. 7
`
`
`
`Patent Application Publication Jul. 5, 2018 Sheet 7 of 61
`
`US 2018/0186872 Α1
`
`L11 FC (RNA-seq)
`
`FIG. 3Ε
`
`FIG. 4Α
`
`Lassen - Exhibit 1011, p. 8
`
`
`
`Patent Application Publication Jul. 5, 2018 Sheet 8 of 61
`
`US 2018/0186872 Α1
`
`FIG. 4Β
`
`hours
`
`FIG. 4C
`
`Measure [pg/mT
`
`IL11 [pg/ml]
`
`Lassen - Exhibit 1011, p. 9
`
`
`
`Patent Application Publication Jul. 5, 2018 Sheet 9 of 61
`
`US 2018/0186872 Α1
`
`■"*>
`*>
`>
`
`FIG. 4D
`
`Lassen - Exhibit 1011, p. 10
`
`
`
`Patent Application Publication Jul. 5, 2018 Sheet 10 of 61 US 2018/0186872 Α1
`
`Stimulus
`
`aSMA
`
`Activated
`
`TGF81
`
`IL11
`
`Stimulus
`
`Collagen
`
`ECM Production
`
`TGFB1
`
`1L11
`
`Stimulus
`
`TGFB1
`
`!L11
`
`1
`
`2 a
`
`FIG. 5Α
`
`Lassen - Exhibit 1011, p. 11
`
`
`
`Patent Application Publication Jul. 5, 2018 Sheet 11 of 61 US 2018/0186872 Α1
`
`ω
`
`Collagen Protein (Sirius Rad)
`
`★★■an*
`
`K>
`
`■
`
`Control TGFBI fill
`
`FIG. 5Β
`
`i________i________f________L
`
`IL6pg/miJ
`
`~~—i i
`Control TGFBI
`
`t
`!L11
`
`FIG. 5C
`
`Lassen - Exhibit 1011, p. 12
`
`
`
`Patent Application Publication Jul. 5, 2018 Sheet 12 of 61 US 2018/0186872 Α1
`
`&3
`
`4-
`
`4**
`
`Mri
`
`^
`ΠΜΡ1 [ng/mL]
`
`φ
`
`Control TGFB1 111 1
`
`FIG. 5D
`
`Control TGFB1 IL11
`
`FIG. 5Ε
`
`i................t................ℓ................ℓ
`
`W
`
`Lassen - Exhibit 1011, p. 13
`
`
`
`Patent Application Publication
`
`Jul. 5, 2018 Sheet 13 of 61 US 2018/0186872 Α1
`
`Mouse
`Hyman
`™ττττ¾
`■000
`
`10 100
`IL11 [ng/mll
`
`FIG. 5F
`
`Activated Fibroblasts
`
`Lassen - Exhibit 1011, p. 14
`
`
`
`Patent Application Publication Jul. 5, 2018 Sheet 14 of 61
`
`US 2018/0186872 Α1
`
`FIG. 6Α
`
`Dermal
`
`Renal
`
`Lung
`
`Ventricular
`
`Atrial
`
`iseiqoitiy
`
`ECy (Periostin)
`
`ΕCM (Collagen)
`
`Activated Fibroblasts
`
`Lassen - Exhibit 1011, p. 15
`
`
`
`Patent Application Publication Jul. 5, 2018 Sheet 15 of 61
`
`US 2018/0186872 Α1
`
`oose III 1 (IQQpg/kg
`Ang II (2mg/kg/day)
`Saline-Contro
`
`φ
`♦ %
`
`*
`
`FIG. 6Β
`
`KJ
`
`Kid
`
`Heart
`
`f
`
`&
`
`'kit'k'k
`
`τ
`
`τ
`
`Lassen - Exhibit 1011, p. 16
`
`'
`
`
`Patent Application Publication Jul. 5, 2018 Sheet 16 of 61 US 2018/0186872 Α1
`
`r
`CM
`
`τ
`
`Lassen - Exhibit 1011, p. 17
`
`
`
`Patent Application Publication Jul. 5, 2018 Sheet 17 of 61 US 2018/0186872 Α1
`
`antML11
`JsG
`
`FIG, 7Β
`
`Lassen - Exhibit 1011, p. 18
`
`
`
`Patent Application Publication
`
`Jul. 5, 2018 Sheet 18 of 61 US 2018/0186872 Α1
`
`¥ Periostin
`
`^
`^
`ECM Production
`
`TGF81 -
`anti-IL11
`f§G ~~
`
`FIG. 7C
`
`1ℓβ secretion
`** *
`
`ns..
`
`----------!-----------1-----------1-----------1-----------
`
`8■«
`
`3*
`
`ρ
`
`g/mL
`
`οp
`
`I-
`
`TGF81
`antML11
`igG
`
`FIG. 7D
`
`Lassen - Exhibit 1011, p. 19
`
`
`
`Patent Application Publication Jul. 5, 2018 Sheet 19 of 61 US 2018/0186872 Α1
`
`FIG. 7Ε
`
`antMU 1
`
`'
`
`4-
`
`FIG. 7F
`
`Lassen - Exhibit 1011, p. 20
`
`
`
`Patent Application Publication
`
`Jul. 5, 2018 Sheet 20 of 61 US 2018/0186872 Α1
`
`FIG. 8Α
`
`FIG. 8Β
`
`Lassen - Exhibit 1011, p. 21
`
`
`
`Patent Application Publication Jul. 5, 2018 Sheet 21 of 61 US 2018/0186872 Α1
`
`4*
`
`FIG. 9
`
`*8*1:30 &IL1tRA
`Mm iMmm
`33 met SG met
`?—
`?—
`
`—s—
`
`-a+
`
`W81
`
`iptjqojqy
`
`Fusion Receptor
`
`anti-IL11 antibody
`
`MW'
`
`111 IRA
`
`Lassen - Exhibit 1011, p. 22
`
`
`
`Patent Application Publication Jul. 5, 2018 Sheet 22 of 61 US 2018/0186872 Α1
`
`FIG. 10Β
`
`Lassen - Exhibit 1011, p. 23
`
`
`
`Patent Application Publication Jul. 5, 2018 Sheet 23 of 61 US 2018/0186872 Α1
`
`Collagen 1 (Intensity/area)
`
`ο
`
`
`
`m
`
`CM
`
`
`
`οο
`
`
`
`
`CM
`
`m
`
`
`
`ο
`
`
`
`οο
`
`FIG. 10D
`
`Lassen - Exhibit 1011, p. 24
`
`
`
`Patent Application Publication Jul. 5, 2018 Sheet 24 of 61 US 2018/0186872 Α1
`
`FIG. 11Β
`
`Lassen - Exhibit 1011, p. 25
`
`
`
`Patent Application Publication Jul. 5, 2018 Sheet 25 of 61 US 2018/0186872 Α1
`
`Collagen - ΗΡΑ
`
`Οοΐ1Α2
`
`FIG. 12Β
`
`RMA Expression
`
`Lassen - Exhibit 1011, p. 26
`
`
`
`Patent Application Publication Jul. 5, 2018 Sheet 26 of 61 US 2018/0186872 Α1
`
`aSMA
`
`flhromcim
`
`FIG. 12D
`
`RNA Expression
`
`RNA Express^
`
`Lassen - Exhibit 1011, p. 27
`
`
`
`Patent Application Publication Jul. 5, 2018 Sheet 27 of 61 US 2018/0186872 Α1
`
`Day 0
`
`7
`
`14
`
`21
`
`SubcwSanaotss
`Bieomyda
`
`FIG. 13Β
`
`20 <~ mics
`
`Lassen - Exhibit 1011, p. 28
`
`
`
`Patent Application Publication Jul. 5, 2018 Sheet 28 of 61 US 2018/0186872 Α1
`
`Eye Fibrosis
`
`WT mice (rr~ 7}
`
`κ
`
`!L11
`
`WT mice (n~7)
`
`WT mice in~7}
`
`ΚΟ mice (η≈7)
`
`; Wound healing/Fidrcsis ;
`
`k
`k
`; IL11
`; 1L11
`<Wound hsailng/Fibrosis j
`:
`* with standard !Lti
`............. ΐ...................................... v...................
`
`............ W‘
`
`: Losa-Gf-futi-ctiort^:
`
`; Wound dealing/Fidfosis ;
`5
`with ft.11
`:
`ΐ Wound hseiing/Fibresis ;
`............. ;............ wojLii............ :...................
`
`FIG. 13C
`
`*
`
`Sacrifice
`
`Lassen - Exhibit 1011, p. 29
`
`
`
`Patent Application Publication Jul. 5, 2018 Sheet 29 of 61 US 2018/0186872 Α1
`
`Regulated by
`* 1L11
`* TGFB1
`* TGFB1 & IL11
`
`Fold change (TGF81 / unstimulated)
`FIG. 14Α
`
`♦ \
`
`*\ »
`Μi
`
`♦ V d
`
`*
`
`* Independent of lift RA
`{η·-359)
`* Mat found without
`h.rmA /«-59;
`
`W! cells; Fold change fTGF81 / unstimulated)
`
`FIG. 14Β
`
`Fold change (IL11 / unstimuiated)
`
`KG cells: Fold change (TGF81 f unstimulated)
`
`Lassen - Exhibit 1011, p. 30
`
`
`
`Patent Application Publication Jul. 5, 2018 Sheet 30 of 61 US 2018/0186872 Α1
`
`!L11RA(+/+) IL11RA C~/~)
`
`FIG. 15
`
`Lassen - Exhibit 1011, p. 31
`
`
`
`Patent Application Publication Jul. 5, 2018 Sheet 31 of 61 US 2018/0186872 Α1
`
`BSO-1E3 1
`
`DVVMTQIPLSLSVSMKFQASISCRSSQSLVHSNGNTYLHWYLQKPGQSPKLLIYKVSNRFS
`GVPDRFSGSGSGTDFTLKISRVEAEDLGVYFCSQSTHVPLTFGAGTKLELK (SEQ ID ΝΟ:1)
`
`LC-CDR1
`LC-CDR2
`LC-CDR3
`
`QSLVHSNGNTY
`KVS
`SQSTHVPLT
`
`{SEQ ID ΝΟ:19)
`{SEQ ID ΝΟ:20)
`{SEQ ID ΝΟ:21)
`
`BSO-1E3 2
`
`NIVMTQSPKSMSMSVGERVTLSCKASENVGTYVSWYQQKPEQSPKLUYGASNRYTGVPD
`RFTGSGSATDFTLTISSVQAEDLADYHCGQGYSYPYTFGGGTKLEIK (SEQ ID ΝΟ:2)
`
`LC-CDR1
`LC-CDR2
`LC-CDR3
`
`ENVGTY
`GAS
`GQGYSYPYT
`
`{SEQ ID ΝΟ:22)
`{SEQ ID ΝΟ:23)
`{SEQ ID ΝΟ:24)
`
`BSO-2E5
`
`DIQMTQSPSSLSASLGERVSLTCRASQDIGSSLNWLQQEPDGTIKRLIYATASLESGVPKRF
`SGSRSGSDYSLTISRLESEDFVDYYCQQYASSPPTFGAGTKLELK {SEQ ID ΝΟ:3)
`
`LC-CDR1: QDIGSS
`LC-CDR2: AT A
`LC-CDR3: QQYASSPPT
`
`ID ΝΟ:25)
`(SEQ
`ID ΝΟ:26)
`(SEQ
`{SEQ ID ΝΟ:27)
`
`BSO-4G3
`
`DIVLTQSPASLAVSLGQSVTiSCRASESVEYSGTTLMQWYQQKPGQPPKLLlYGASIMVESG
`VPARFSGSGSGTDFSLNIHPVEEDDIAMYFCQQSRKVPYTFGSGTKLEIK (SEQ ID ΝΟ:4)
`
`LC-CDR1:
`LC-CDR2:
`LC-CDR3:
`
`ESVEYSGTTL
`GAS
`QQSRKVPYT
`
`(SEQ ID ΝΟ:28)
`{SEQ ID ΝΟ:23)
`(SEQ ID ΝΟ:29)
`
`FIG. 16
`
`Lassen - Exhibit 1011, p. 32
`
`
`
`Patent Application Publication
`
`Jul. 5, 2018 Sheet 32 of 61
`
`US 2018/0186872 Α1
`
`BSO-5E5
`
`DSVMSQSPSSLPVSVGENVTMSCKSSQSLLYGSNQKNYLAWYQQKPGQSPKLLiYWASTR
`ESGVPDRFTGSGSGTDFTLTISSVKAEDLAVYFCQQYYSYPRTFGGGTKLEIK (SEQ ID
`ΝΟ:5)
`
`LC-CDR1
`LC-CDR2
`LC-CDR3
`
`QSLLYGSNQKNY
`WAS
`QQYYSYPRT
`
`(SEQ ID ΝΟ:30)
`(SEQ ID ΝΟ:31)
`(SEQ ID ΝΟ:32)
`
`BSO-7G9
`
`DVVMTQTPLSLPVSLGDQASISCRSSQSLVHSNGNTYLHWYLQKPGQSPKLLIYKVSNRFS
`GVPDRFSGSGSGTDFTLKiSRVEAEDLGVYFCSQSTHVPLTFGAGTKLELK (SEQ ID ΝΟ:6)
`
`LC-CDR1
`LC-CDR2
`LC-CDR3
`
`QSLVHSNGNTY
`KVS
`SQSTHVPLT
`
`(SEQ ID ΝΟ:19)
`(SEQ ID ΝΟ:20)
`(SEQ ID 1Μ0:21)
`
`BSO-9A7
`
`DIVLTQSPATLSMTPGDSVSLSCRASQSISNNLHWYQQKSHESPRLLIKYASQSISGIPSRFS
`GSGSGTDFTLSFNSVETEDFGVYFCQQRYSWPLTFGAGTKLEMK (SEQ ID ΝΟ:7)
`
`LC-CDR1
`LC-CDR2
`LC-CDR3
`
`QSISNN
`YAS
`QQRYSWPLT
`
`(SEQ ID ΝΟ:33)
`(SEQ ID ΝΟ:34)
`(SEQ ID ΝΟ:35)
`
`BSO-1QD11
`
`DIQMTQSPSSLSASLGERVSLTCRASQEISAYLSWLQQKPDGTIKRLIYSTSTLDSGVPKRF
`SGSRSGSDYSLTISSLESEDFADYFCLQYASSPLTFGAGTKLELK (SEQ ID ΝΟ:8)
`
`LC-CDR1: QEISAY
`LC-CDR2:
`STS
`LC-CDR3:
`LQYASSPLT
`
`(SEQ ID ΝΟ:36)
`(SEQ ID ΝΟ:37)
`(SEQ ID ΝΟ:38)
`
`FIG. 16 (Cont.)
`
`Lassen - Exhibit 1011, p. 33
`
`
`
`Patent Application Publication
`
`Jul. 5, 2018 Sheet 33 of 61
`
`US 2018/0186872 Α1
`
`BSQ-13B10
`
`DIVMTQSQKFMSTSVGDRVSVTCKASQNVGSNVAWYQQKAGQSPKALIYSASYRYSGVP
`DRFTGSGSGTDFTLTISNVQSEDLAEYFCQQYNSYPLTFGAGTKLELK (SEQ ID ΝΟ:9)
`
`LC-CDR1:
`LC-CDR2:
`LC-CDR3:
`
`QNVGSN
`SAS
`QQYNSYPLT
`
`(SEQ ID ΝΟ:39}
`(SEQ ID ΝΟ:40)
`(SEQ ID ΝΟ:41)
`
`FIG. 16 (Cont.)
`
`Lassen - Exhibit 1011, p. 34
`
`
`
`Patent Application Publication Jul. 5, 2018 Sheet 34 of 61 US 2018/0186872 Α1
`
`BSO-1E3 1
`
`QVQLQQPGAELVTPGASVKLSCKASGFTFTNNWMHWVKQRPGQGLEWIGMIHPNSGITNI
`NEKFKNKATVTVDKSSSTVYIQLSSLTSEDSAVYYCRSDGTYEGYFDYWGQGTPLTVSS
`(SEQ ID ΝΟ:10)
`
`HC-CDR1: GFTFTNNW
`HC-CDR2:
`IHPNSGIT
`HC-CDR3: RSDGTYEGYFDY
`
`(SEQ ID ΝΟ:42)
`{SEQ ID ΝΟ:43)
`(SEQ ID ΝΟ:44)
`
`BSO-1E3 2
`
`QVQLQQSGPELVKPGASVKISCKASGYNFNDYYINWVNQRPGQGLEWIGWIFPGRUTYYN
`EKFKGKATLTVDTSSNTAYMLLSSLTSEDSAVYFCARGVGEGFDYWGQGTTLTVSS (SEQ
`ID ΝΟ:11)
`
`HC-CDR1:
`HC-CDR2:
`HC-CDR3:
`
`GYNFNDYY
`IFPGRIIT
`ARGVGEGFDY
`
`(SEQ ID ΝΟ:45)
`(SEQ ID ΝΟ:46)
`(SEQ ID ΝΟ:47)
`
`BSO-2E5
`
`QGQVQQSGAELVKPGASVKLSCKTSGFTFSTSYISWLKQKPRQSLEWIAWIYAGTGSTSYN
`QKFTGKAQLTVDTSSSTAYMQLSSLTSEDSAlYYCARHWAYWGQGTLVTVSA (SEQ ID
`ΝΟ:12)
`
`HC-CDR1:
`HC-CDR2:
`HC-CDR3:
`
`GFTFSTSY
`IYAGTGST
`ARHWAY
`
`(SEQ ID ΝΟ:48)
`(SEQ ID ΝΟ:49)
`(SEQ ID ΝΟ:50)
`
`BSO-4G3
`
`EVQLVESGGGLVKPGGSLKLSCAASGFTFSTYAMSWVRQTPEKRLEWVAAIKSNGGSTYY
`PDTVKDRFTISRDNAKNTLYLQMSSLRPEDTALYYCAHGLLFAHWGQGTLVTVSA (SEQ ID
`ΝΟ:13)
`
`HC-CDR1:
`HC-CDR2:
`HC-CDR3:
`
`GFTFSTYA
`IKSNGGST
`AHGLLFAH
`
`(SEQ ID ΝΟ:51)
`(SEQ ID ΝΟ:52)
`(SEQ ID ΝΟ:53)
`
`FIG. 17
`
`Lassen - Exhibit 1011, p. 35
`
`
`
`Patent Application Publication
`
`Jul. 5, 2018 Sheet 35 of 61
`
`US 2018/0186872 Α1
`
`BSO-5E5
`
`DVQLQESGPGLVKPSQSLSLTCSVTGYSITSDYYWNWIRQFPGNKLEWMGYISYDSSNNY
`NPSLKNR1SITRDTSKNQFFLKLNSVTTEDTATYYCASVGYYYVSDWYFDVWGTGTTVTVS
`S (SEQ ID ΝΟ:14)
`
`HC-CDR1: GYSITSDYY
`HC-CDR2:
`ISYDSSN
`HC-CDR3: ASVGYYYVSDWYFDV
`
`(SEQ ID ΝΟ:54)
`(SEQ ID ΝΟ:55)
`(SEQ ID ΝΟ:56)
`
`BSO-7G9
`
`QVQLQQPGAELVKPGASVRLSCKASGYTFTSYWMHWVKQRPGQGLEWIGMIHPNSGYTN
`YNEKFKIKATLTVDKSSSTAHMQLSSLTSEDSAVYHCARGGYDGSYGPWFAYWGQGTLVT
`VS A {SEQ ID ΝΟ:15)
`
`HC-CDR1: GYTFTSYW
`HC-CDR2:
`IHPNSGYT
`HC-CDR3: ARGGYDGSYGPWFAY
`
`(SEQ ID ΝΟ:57)
`(SEQ ID ΝΟ:58)
`(SEQ ID ΝΟ:59)
`
`BSO-9A7
`
`QVQLQQPGAELVRPGSSVKLSCKASGYTFTNYWMHWLKQRPVQGLEWIGNIGPSDSKTH
`YNQKFKDKATLTVDKSSSTAYMQLNSLTSEDSAVYYCARGDYVLFTYWGQGTLVTVSA
`(SEQ ID ΝΟ:16)
`
`HC-CDR1
`HC-CDR2
`HC-CDR3
`
`GYTFTNYW
`IGPSDSKT
`ARGDYVLFTY
`
`(SEQ ID ΝΟ:60)
`(SEQ ID ΝΟ:61)
`(SEQ ID ΝΟ:62)
`
`BSO-1QD11
`
`QVQLQQSGTELVRPGTSVKMSCKAAGYTFTPYWIGWIKQRPGHGLEWIGPIFPGGDYTKC
`SERFKGKAKLTADTSSSTAYMQLSRLTSEDSAIYYCARRSTTIRFGAMDNWGQGTSVTVSS
`(SEQ ID NO: 17)
`
`HC-CDR1: GYTFTDYW
`HC-CDR2:
`IFPGGDYT
`HC-CDR3: ARRSTTIRFGAMDN
`
`(SEQ ID ΝΟ:63)
`(SEQ ID ΝΟ:64)
`(SEQ ID ΝΟ:65)
`
`FIG. 17 (Cont.)
`
`Lassen - Exhibit 1011, p. 36
`
`
`
`Patent Application Publication Jul. 5, 2018 Sheet 36 of 61 US 2018/0186872 Α1
`
`BSQ-13B10
`
`QVQLKESGPGLVAPSQSLSITCTVSGFSLTSFSISWVRQPPGKGLEWLGGIWTGGGTNYN
`SALKPRLSISKDNSKSQVFLKMNSLQTDDTARYYCARNSNYPSGFAYWGQGTLVTVSA
`(SEQ ID ΝΟ:18)
`
`HC-CDR1:
`HC-CDR2:
`HC-CDR3:
`
`GFSLTSFS
`IWTGGGT
`ARNSNYPSGFAY
`
`(SEQ ID ΝΟ:66)
`(SEQ ID ΝΟ:67)
`(SEQ ID ΝΟ:68)
`
`FIG. 17 (Cont.)
`
`Lassen - Exhibit 1011, p. 37
`
`
`
`Patent Application Publication Jul. 5, 2018 Sheet 37 of 61 US 2018/0186872 Α1
`
`CDR 1
`
`QSLVHSNGNTY (SEQ ID
`ΝΟ:19)
`ENVGTY (SEQ ID ΝΟ:22)
`
`QDIGSS (SEQ ID ΝΟ:25)
`
`ESVEYSGTTL (SEQ ID
`ΝΟ:28)
`QSLLYGSNQKNY (SEQ ID
`ΝΟ:30)
`QSLVHSNGNTY (SEQ ID
`ΝΟ:19)
`QSISNN (SEQ ID ΝΟ:33)
`
`CDR 2
`Li ght Chain
`KVS (SEQ ID
`ΝΟ:20)
`GAS (SEQ ID
`ΝΟ:23)
`ΑΤΑ (SEQ ID
`ΝΟ:26)
`GAS (SEQ ID
`ΝΟ:23)
`WAS (SEQ ID
`ΝΟ:31)
`KVS (SEQ ID
`ΝΟ:20)
`YAS (SEQ ID
`ΝΟ:34)
`STS (SEQ ID
`ΝΟ:37)
`SAS (SEQ ID
`ΝΟ:40)
`
`Clone
`
`BSO-1 E3_1
`
`BSO-1 E3_2
`
`BSO-2E5
`
`BSO-4G3
`
`BSO-5E5
`
`BSO-7G9
`
`BSO-9A7
`
`BSO-13Β10
`
`Clone
`
`BSO-1 E3_1
`
`BSO-1 E3_2
`
`BSO-2E5
`
`BSO-4G3
`
`BSO-5E5
`
`BSO-7G9
`
`BSO-9A7
`
`BSO-10D11
`
`BSO-13Β10
`
`BSO-10D11
`
`QEISAY (SEQ ID ΝΟ:36)
`
`QNVGSN (SEQ ID ΝΟ:39)
`
`FIG. 18
`
`CDR 1
`
`CDR 2
`Heavy Chain
`GFTFTNNW (SEQ ID ΝΟ:42)
`IHPNSGIT (SEQ
`ID ΝΟ:43)
`IFPGRIIT (SEQ ID
`ΝΟ:46)
`IYAGTGST (SEQ
`ID ΝΟ:49)
`IKSNGGST (SEQ
`ID ΝΟ:52)
`ISYDSSN (SEQ ID
`ΝΟ:55)
`IHPNSGYT (SEQ
`ID ΝΟ:58)
`IGPSDSKT (SEQ
`ID ΝΟ:61)
`IFPGGDYT (SEQ
`ID ΝΟ:64)
`IWTGGGT (SEQ
`ID ΝΟ:67)
`
`GYNFNDYY (SEQ ID ΝΟ:45)
`
`GFTFSTSY (SEQ ID ΝΟ:48)
`
`GFTFSTYA (SEQ ID ΝΟ:51)
`
`GYSITSDYY (SEQ ID
`ΝΟ:54)
`GYTFTSYW (SEQ ID ΝΟ:57)
`
`GYTFTNYW (SEQ ID ΝΟ:60)
`
`GYTFTDYW (SEQ ID ΝΟ:63)
`
`GFSLTSFS (SEQ ID ΝΟ:66)
`
`FIG. 19
`
`CDR 3
`
`SQSTHVPLT (SEQ ID ΝΟ:21)
`
`GQGYSYPYT (SEQ ID ΝΟ:24)
`
`QQYASSPPT (SEQ ID ΝΟ:27)
`
`QQSRKVPYT (SEQ ID ΝΟ:29)
`
`QQYYSYPRT (SEQ ID ΝΟ:32)
`
`SQSTHVPLT (SEQ ID ΝΟ:21)
`
`QQRYSWPLT (SEQ ID ΝΟ:35)
`
`LQYASSPLT (SEQ ID ΝΟ:38)
`
`QQYNSYPLT (SEQ ID ΝΟ;41)
`
`CDR 3
`
`RSDGTYEGYFDY (SEQ ID
`ΝΟ:44)
`ARGVGEGFDY (SEQ ID
`ΝΟ:47)
`ARHWAY (SEQ ID ΝΟ:50)
`
`AHGLLFAH (SEQ ID ΝΟ:53)
`
`ASVGYYYVSDWYFDV (SEQ ID
`ΝΟ:56)
`ARGGYDGSYGPWFAY (SEQ
`ID ΝΟ:59)
`ARGDYVLFTY (SEQ ID ΝΟ:62)
`
`ARRSTTIRFGAMDN (SEQ ID
`ΝΟ:65)
`ARNSNYPSGFAY (SEQ ID
`ΝΟ:68)
`
`Lassen - Exhibit 1011, p. 38
`
`
`
`Patent Application Publication
`
`Jul. 5, 2018 Sheet 38 of 61
`
`US 2018/0186872 Α1
`
`Cione(s)
`BSO-9A7
`BSO-10D11
`BSO-13B10
`BSO-2E5
`
`LC-CDR1
`
`QSISNN (SEQ ID ΝΟ:33)
`QEISAY (SEQ ID ΝΟ:36)
`QNVGSN (SEQ ID ΝΟ:39)
`QDIGSS (SEQ ID ΝΟ:25)
`
`Sequence
`family
`LC-CDR1-1
`
`BSO-5E5
`BSO-1E3 1,
`BSO-7G9
`
`QSLLYGSNQKNY (SEQ ID ΝΟ:30)
`QSLVHSNGNTY (SEQ ID ΝΟ:19)
`
`LC-CDR1-2
`
`BSO-4G3
`
`ESVEYSGTTL (SEQ ID ΝΟ:28)
`
`BSO-1E3 2
`
`ENVGTY (SEQ ID ΝΟ:22)
`
`LC-CDR1-3
`
`LC-CDR1-4
`
`FIG. 20Α
`
`Family Consensus
`
`QX1X2X3X4X5 (SEQ ID
`ΝΟ:69)
`
`Χ1 = Ν, S, Ε or D
`X2 = I or V
`X3 = G or S
`X4 = S, Ν or A
`X5 = Ν, Υ or S
`QSLXsXvXeSNXgX.oX.iY
`(SEQ ID ΝΟ:70)
`
`Χβ = Absent or L
`X7 = V or Υ
`Xa ≈ Η or G
`Xa = G or Q
`Χ,ο ≈ Ν or Κ
`Xu ≈ T or Ν
`ESVEYSGTTL (SEQ ID
`ΝΟ:28)
`ENVGTY (SEQ ID ΝΟ:22)
`
`Clone(s)
`BSO-4G3,
`BSO-1 E3_2
`BSO-5E5
`BSO-9A7
`BSO-13Β10
`BSO-10D11
`BSO-1 Ε3 1,
`BSO-7G9
`
`LC-CDR2
`
`GAS (SEQ ID ΝΟ:23)
`
`WAS (SEQ ID ΝΟ:31)
`YAS (SEQ ID ΝΟ:34)
`SAS (SEQ ID ΝΟ:40)
`STS (SEQ ID ΝΟ:37)
`KVS (SEQ ID ΝΟ:20)
`
`Sequence
`family
`LC-CDR2-1
`
`LC-CDR2-2
`
`~BSO-2E5
`
`AT A(SI”QTDN0:26j
`
`LC-CDR2-3
`
`Family Consensus
`
`X12AS (SEQ ID
`ΝΟ:71)
`
`X,2 = G, W,YorS
`
`X)3Xi4S (SEQ ID
`ΝΟ:72}
`
`Χ,3 ≈ S or Κ
`X)4 ≈ Τ or V
`ATA (SEQ ID ΝΟ:26)
`
`FIG. 20Β
`
`Lassen - Exhibit 1011, p. 39
`
`
`
`Patent Application Publication
`
`Jul. 5, 2018 Sheet 39 of 61
`
`US 2018/0186872 Α1
`
`Clone(s)
`
`BSO-1 E3_1,
`BSO-7G9
`BSO-1 E3_2
`BSO-2E5
`BSO-4G3
`BSO-5E5
`BSO-9A7
`BSO-10D11
`BSO-13Β10
`
`LC-CDR3
`
`SQSTHVPLT (SEQ ID ΝΟ:21)
`
`GQGYSYPYT (SEQ ID ΝΟ:24)
`QQYASSPPT (SEQ ID ΝΟ:27)
`QQSRKVPYT (SEQ ID ΝΟ:29)
`QQYYSYPRT (SEQ ID ΝΟ:32)
`QQRYSWPLT (SEQ ID ΝΟ:35)
`LQYASSPLT (SEQ ID ΝΟ:38)
`QQYNSYPLT (SEQ ID ΝΟ:41)
`
`FIG. 20C
`
`Sequence
`family
`LC-CDR3-1
`
`Family Consensus
`
`X,5QXl6Xl7Xl8Xl9PX2oT
`(SEQ ID ΝΟ:73)
`
`Χ15 ≈ Q, S, G or L
`Χΐ6 = Υ, S, G or R
`Χ17 = Υ, A, Τ, Ν or R
`Χΐβ ≈ S, Η or Κ
`Χΐ9 = V, Υ, S or W
`X20 ≈ L, Υ, R or Ρ
`
`Clone(s)
`
`BSO-7G9
`BSO-9A7
`BSO-10D11
`BSO-2E5
`BSO-4G3
`BSO-1 E3_1
`
`HC-CDR1
`
`GYTFTSYW (SEQ ID ΝΟ:57)
`GYTFTNYW (SEQ ID ΝΟ;60)
`GYTFTDYW (SEQ ID ΝΟ:63)
`GFTFSTSY (SEQ ID ΝΟ:48)
`GFTFSTYA (SEQ ID ΝΟ:51)
`GFTFTNNW (SEQ ID ΝΟ:42)
`
`Sequence
`family
`HC-CDR1-1
`
`HC-CDR1-2
`
`BSO-5E5
`BSO-1 E3_2
`
`GYSITSDYY (SEQ ID ΝΟ:54)
`GYNFNDYY (SEQ ID ΝΟ:45)
`
`HC-CDR1-3
`
`BSO-13Β10
`
`GFSLTSFS (SEQ ID ΝΟ:66)
`
`HC-CDR1-4
`
`FIG. 21A
`
`Family Consensus
`
`GYTFTXa,YW (SEQ ID
`ΝΟ:74)
`
`Χ21 = S, Ν or D
`GFTFX22X23X24X25
`(SEQ ID ΝΟ:75)
`
`Χ22 = S or Τ
`Χ23 ≈ Τ or Ν
`X24 = S, Υ or Ν
`Χ25 = Υ, A or W
`GYX26X27X2BX29DYY
`(SEQ ID ΝΟ:76)
`
`Χ26 ≈ S or Ν
`Χ27 = I or F
`Χ28 = Τ or IM
`Χ29 = Absent or S
`GFSLTSFS (SEQ ID
`ΝΟ:66)
`
`Lassen - Exhibit 1011, p. 40
`
`
`
`Patent Application Publication Jul. 5, 2018 Sheet 40 of 61 US 2018/0186872 Α1
`
`Clone(s)
`
`HC-CDR2
`
`BSO-1 E3_1
`BSO-4G3
`BSO-2E5
`BSO-7G9
`
`IHPNSGIT (SEQ ID ΝΟ:43)
`IKSNGGST (SEQ ID ΝΟ:52)
`IYAGTGST (SEQ ID ΝΟ:49)
`IHPNSGYT (SEQ ID ΝΟ:58)
`
`Sequence
`family
`HC-CDR2-1
`
`Family Consensus
`
`IX30X31X32X33GX34T (SEQ ID
`ΝΟ:77)
`
`BSO-1 E3_2
`BSO-10D11
`
`IFPGRIIT (SEQ ID ΝΟ:46)
`IFPGGDYT (SEQ ID ΝΟ:64)
`
`HC-CDR2-2
`
`BSO-5E5
`BSO-9A7
`BSO-13Β10
`
`ISYDSSN (SEQ ID ΝΟ:55)
`IGPSDSKT (SEQ ID ΝΟ:61)
`IWTGGGT (SEQ ID ΝΟ:67)
`
`HC-CDR2-3
`HC-CDR2-4
`HC-CDR2-5
`
`Χ30 = Η, KorY
`Χ31 = Ρ, Sor A
`Χ32 = Ν or G
`Χ33 ≈ S, G or Τ
`Χ34 = S, 1 or Υ
`IFPGXasXseXsyT (SEQ ID
`ΝΟ:78)
`
`Χ35 = R or G
`Χ36 = 1 or D
`Χ37 = 1 or Υ
`ISYDSSN (SEQ ID ΝΟ:55)
`IGPSDSKT (SEQ ID ΝΟ:61)
`IWTGGGT (SEQ ID ΝΟ:67)
`
`FIG. 21Β
`
`Sequence
`family
`HC-GDR3-1
`
`Clone(s)
`
`HC-CDR3
`
`BSO-7G9
`
`ARGGYDGSYGPWFAY
`(SEQ ID ΝΟ:59)
`BSO-1 E3_2 ARGVGEGFDY (SEQ ID
`ΝΟ:47)
`ARGDYVLFTY (SEQ ID
`ΝΟ:62)
`
`BSO-9A7
`
`BSO-5E5
`
`BSO-2E5
`BSO-4G3
`
`BSO-1 E3_1
`
`BSO-10D11
`
`ASVGYYYVSDWYFDV
`(SEQ ID ΝΟ:56)
`ARHWAY (SEQ ID ΝΟ:50) HC-CDR3-3
`AHGLLFAH (SEQ ID
`HC-CDR3-4
`ΝΟ;53)
`RSDGTYEGYFDY(SEQ
`ID ΝΟ:44)
`BSO-13Β10 ARNSNYPSGFAY(SEQ
`ID ΝΟ:68)
`ARRSTTIRFGAMDN (SEQ
`ID ΝΟ:65)
`
`HC-CDR3-2
`
`HC-CDR3-5
`
`HC-CDR3-6
`
`HC-CDR3-7
`
`FIG. 21C
`
`Family Consensus
`
`A RGX38X39 Χ40Χ41X42X43X44X45X4SFX47Y
`(SEQ ID ΝΟ:79)
`
`X38 = Absent, D or G
`Χ39 ≈ Absent or Υ
`Χ40 = V or D
`Χ41 = G or L
`Χ42 = Absent, Ε or S
`Χ43 = Absent or Υ
`Χ44 = Absent or G
`Χ45 = Absent or Ρ
`Χ46 = Absent or W
`Χ47 = D, Τ or A
`ASVGYYYVSDWYFDV (SEQ ID
`ΝΟ:56)
`ARHWAY (SEQ ID ΝΟ:50)
`AHGLLFAH (SEQ ID ΝΟ:53)
`
`RSDGTYEGYFDY (SEQ ID ΝΟ:44)
`
`ARNSNYPSGFAY (SEQ ID ΝΟ:68)
`
`ARRSTTIRFGAMDN (SEQ ID ΝΟ:65)
`
`Lassen - Exhibit 1011, p. 41
`
`
`
`Patent Application Publication
`
`Jul. 5, 2018 Sheet 41 of 61
`
`US 2018/0186872 Α1
`
`BSO-1E3 1
`
`GAT GTT GT GAT G ACCCAAATTCCACT CT CCCTGT CT GT CAGT AT GAAGTT GCAAGCCT C
`CAT CT CTT GCAGAT CT AGT C AGAGCCTT GT ACACAGT ΑΑΤ GGAAACACCT ΑΤΤΤ ACATT G
`GT ACCTG C AG AAG CC AGGCC AGT CT CC AAAGCT CCT GAT CT AC AAAGTTT CC A ACCG AT
`ΤΤΤ CT GGGGT CCCAGACAGGTT CAGT GGCAGTGG AT CAGGG ACAG ΑΤΤΤ C ACACT CAA
`GAT CAGC AG AGT GG AGGCTG AGG ATCT GGG AGTTTΑΤΤΤ CT G CT CT CA AAGT AC AC AT G
`ΤΤCCGCTCACGTTCGGTGCTGGGACCAAGCTGGAGCTGAAA (SEQ ID ΝΟ:80)
`
`BSO-1E3 2
`
`AAC ATTGT A AT G ACCCA AT CT CCCAA AT CCAT GTCCAT GT CAGT AGG AG AG AGGGT CAC
`CTT G AGCT GC AAGGCCAGT GAG A AT GT GGGT ACTT AT GT AT CCT GGT AT C AAC AGAAAC
`C AGAGCAGT CTCCT AAACT GCT GAT AT ACGGGGCAT CCAACCGGT ACACT GGGGTCCC
`CGATCGCTTCACAGGCAGTGGATCTGCAACAGATTTCACTCTGACCATCAGCAGTGTG
`CAGGCT GAAG ACCTT GCAGATT AT CACT GT GG ACAGGGTT AC AGCT AT CCGT ACACGTT
`CGGAGGGGGGACCAAGCTGGAAATAAAA (SEQ ID ΝΟ:81)
`
`BSO-2E5
`
`GACAT CCAGATGACCCAGT CTCCATCCT CCTT ATCTGCCTCT CTGGGAGAAAG AGTCAG
`TCTCACTTGTCGGGCAAGTCAGGACATTGGTAGTAGCTTAAACTGGCTTCAGCAGGAAC
`CAGAT GGAACT ATT AAACGCCT GAT CT ACGCCACAGCCAGTTT AG ΑΑΤ CT GGTGT CCCC
`AAAAGGTT CAGT GGCAGT AGGT CTGGGT GAG ACT ATT CT CT CACC AT C AGCAG ACTT G A
`GT CTG AAG ΑΤΤΤΤ GT AG ACT ATT ACT GT CAACAAT AT GCT AGCT CTCCTCCCACGTT CGG
`Τ GCTGGG ACC AAGCT GGAGCT GAAA (SEQ ID ΝΟ:82)
`
`BSO-4G3
`
`G ACATT GTGCT CACCCAAT CT CCAGCTT CTTT GGCT GT GT CT CT AGGGCAG AGTGTC AC
`CAT CT CCT GC AG AGCCAGT G A AAGT GTT G ΑΑΤ ATT CT GGC ACT ACTTT A AT GC AGTGGT
`ACCAACAG AAACCAGGAC AGCCACCCAAACTCCT CAT CT AT GGTGCATCCAACGT AG ΑΑ
`Τ CT GGGGTCCCT GCCAGGTTT AGT GGCAGT GGGT CT GGG AC AGACTT CAGCCTCAACA
`Τ CCATCCT GT GG AGG AGG ATG AT ATT GCAAT GT ΑΤΤΤ CT GT C AGCAAAGT AGG AAGGTT
`CCGTAT ACGTT CGG AT CGGGG ACCA AGCT GG ΑΑ AT ΑΑΑΑ (SEQ ID ΝΟ:83)
`
`FIG. 22Α
`
`Lassen - Exhibit 1011, p. 42
`
`
`
`Patent Application Publication
`
`Jul. 5, 2018 Sheet 42 of 61 US 2018/0186872 Α1
`
`BSO-5E5
`
`G AC ATT GTG AT GT CACAGT CT CC AT CCTCCCT ACCTGTGT CAGTT GG AG AG ΑΑΤGTT AC
`Τ AT G AGCT G C AAGT CCAGT C AG AGCCTTTT ATATGGT AGC ΑΑΤ C AAAAG AACT ACTTGG
`CCTGGT ACC AGC AG AAACC AGGGC AGT CT CCT AAACT GCT G ΑΤΤΤ ACT GGGC AT CCAC
`Τ AGGG ΑΑΤ CT GGGGT CCCT GAT CGCTT CACAGGCAGTGG AT CT GGG ACAG ΑΤΤΤ CACT
`CT CACCAT CAGC AGT GT GAAGGCT G AAG ACCT GGC AGTTT ΑΤΤΤ CTGT CAGCAAT ATT A
`Τ AGCT AT CCT CGG ACGTT CGGTGG AGGCACCAAGCTGG ΑΑΑΤ CAAA (SEG ID ΝΟ:84)
`
`BSO-7G9
`
`GAT GTT GTG ATGACCC AAACT CCACT CT CCCT GCCT GT CAGT CTT GG AGAT CAAGCCT C
`CAT CT CTT GC AG AT CT AGT C AG AGCCTT GT AC AC AGT ΑΑΤ GG A AAC ACCT ΑΤΤΤ AC ATT G
`GTACCTGCAGAAGCCAGGCCAGTCTCCAAAGCTCCTGATCTACAAAGTTTCCAACCGAT
`ΤΤΤ CTGGGGTCCCAGACAGGTT CAGTGGCAGT GGAT CAGGG ACAGATTT CACACT CAA
`GAT CAGCAG AGT GG AGGCTG AGGAT CTGGG AGTTT ΑΤΤΤ CTGCT CTCAAAGT ACACATG
`TTCCGCTCACGTTCGGTGCTGGGACCAAGCTGGAGCTGAAA (SEQ ID ΝΟ:85)
`
`BSO-9A7
`
`GAT ATT GTGCTAACT CAGT CT CC AGCC ACCCT GT CT AT G ACT CC AGG AG AT AGCGT C AG
`TCTTT CCT GCAGGGCCAGCCAAAGT ATT AGCAACAACCTACACT GGT AT CAACAAAAAT
`C ACAT G AGT CT CC AAGGCTT CT CAT CAAGT AT GCTT CCC AGT CC AT CT CT GGG AT CCCC
`Τ CCAGGTT CAGT GGCAGT GGAT CGGGG ACAG ΑΤΤΤ CACT CT CAGTTTCAACAGT GT GG
`AG ACT G AAGATTTT GGAGT GT ΑΤΤΤ CT GT CAACAG AG AT ACAGCT GGCCT CT CACGTT C
`GGTGCT GGG ACC AAGCT GG ΑΑΑΤ G A ΑΑ (SEQ ID ΝΟ:86)
`
`BSO-tOP11
`
`G AC AT CC AG AT G ACCCAGT CT CC AT CCT CCTT ATCTGCCTCTCT GGG AG AAAG AGT C AG
`Τ CT CACTT GT CGGGC AAGT C AGG ΑΑΑΤΤ AGT GCTT ACTT AAGCT GGCTT CAGC AG ΑΑ AC
`CAG AT GG AACT ATT AAACGCCT GAT CT ACAGCACAT CCACTTT AG ATT CT GGTGT CCCA
`AAAAGGTT CAGTGGCAGT AGGT CT GGGT CAGATT ATT CTCT CACCAT CAGCAGCCTT G A
`GTCT G AAG ΑΤΤΤΤ GC AG ACT ΑΤΤΤ CT GT CT CCAAT ATGCT AGTT CT CCGCT CACGTT CGG
`TGCTGGGACCAAGCTGGAGCTGAAA {SEQ ID ΝΟ:87)
`
`FIG. 22Α (Cont.)
`
`Lassen - Exhibit 1011, p. 43
`
`
`
`Patent Application Publication
`
`Jul. 5, 2018 Sheet 43 of 61
`
`US 2018/0186872 Α1
`
`BSQ-13B10
`
`G AC ATT GTGAT G ACCC AGT CT C ΑΑΑΑΑΤΤ CAT GT CC ACAT CAGT AGG AG AC AGGGT C AG
`CGTC ACCTGCAAGGCCAGT CAG ΑΑΤ GT GGGT AGT ΑΑΤ GT AGCCTGGT AT CAACAGAAA
`GG AGGGC ΑΑΤ CT CCT AAAGC ACT G ΑΤΤΤ ACT CGGCAT CCT ACCGGTAC AGT GG AGT CC
`CT GAT CGCTT C AC AGGC AGT GG ATCT GGG ACAG ΑΤΤΤ CACT CT C ACC AT C AGC ΑΑΤ GT G
`CAGT CTGAAG ACTTGGCAG AGT ATTTCTGT CAGCAAT AT AACAGCT ATCCGCT CACGTT
`CGGTGCTGGGACCAAGCTGGAGCTGAAA (SEQ ID ΝΟ:88)
`
`FIG. 22Α (Cont.)
`
`Lassen - Exhibit 1011, p. 44
`
`
`
`Patent Application Publication
`
`Jul. 5, 2018 Sheet 44 of 61
`
`US 2018/0186872 Α1
`
`BSO-1E3 1
`
`CAGGTCCAACTGCAGCAGCCTGGGGCT GAACT GGT CACGGCTGGGGCTT CAGT GAAG
`TTGTCCT GC AAGGCTT CT GGCTT C ACTTT C ACCAACAACTGG AT GCACT GGGT G AAGCA
`GAGACCTGGACAAGGCCTT GAGTGG ATT GGAATGATT CATCCT ΑΑΤ AGTGGGATT ACT A
`ACATCAATGAGAAGTTCAAGAACAAGGCCACAGTGACTGTAGACAAATCCTCCAGCACA
`GT CT ACAT ACAACT CAGCAGCCT G ACAT CT GAGGACT CT GCGGT CT ATT ACT GT CGCTC
`CGATGGTACCTACGAGGGCTACTTTGACTACTGGGGCCAAGGCACCCCTCTCACAGTC
`TCCTCA (SEQ ID ΝΟ:89)
`
`BSO-1E3 2
`
`CAGGTCCAACTACAGCAGTCTGGACGTGAACTGGTGAAGCCTGGGGCTTCAGTGAAGA
`Τ AT CGT GC AAGGCTT CTGGCT ACAATTT C ΑΑΤ G ACT ACT AT ATAAACTGGGT G AACC AG A
`GGCCTGG ACAGGG ACT! G AGT GG ATT GG AT GG ΑΤΤΤΤΤ CCTGG AAG ΑΑΤΤ ATT ACTT AC
`Τ ACAAT GAG ΑΑΑΤΤ CAAGGGC AAGGGC AC ACTT ACT GT AG AC ACAT CCT CCAACACAGC
`CT ACAT GTTGCT CAGCAGCCT GACCT CT GAGGACT CTGCGGTCT ΑΤΤΤ CT GT GCAAGAG
`GGGT AGGAGAGGGCTTTGACT ACTGGGGCCAAGGCACCACT CT CACAGT CT CCT CA
`(SEQ ID ΝΟ:90)
`
`BSO-2E5
`
`CAGGGT CAGGTGCAGCAGT CTGGAGCTGAGCT GGTGAAGCCTGGGGCTT CAGTGAAG
`CT GT CCTGC A AG ACTT CT GGCTT C ACCTT CAGT ACT AGTT AT AT AAGTTGGTT G AAGCA
`GAAGCCT CGACAGAGTCTT GAGTGGATTGCAT GGATTTATGCT GGAACT GGT AGT ACT A
`GCT AT ΑΑΤ CAG ΑΑΑΤΤ CACAGGCAAGGCCCAACT GACT GT AGACACAT CCTCCAGCACA
`GCCT ACATGC A ACT CAGCAGCCT G AC AT CT GAGGACT CTGCCAT CT ATT ACT GTGCAAG
`ACACTGGGCTT ACT GGGGCCAAGGGACT CTGGT CACT GT CT CT GCA (SEQ ID ΝΟ:91)
`
`BSO-4G3
`
`GAGGTGCAGCTGGTGGAGTCTGGGGGAGGCTTAGTGAAGCCTGGCGGGTCCCTGAAA
`CT CT CCT GTGCAGCCTCT GG ATT CACTTT CAGT ACCT ATGCCAT GT CTTGGGTT CGCCA
`GACT CCAGAG AAGAGGCT GG AGT GGGT CGCAGCCATT AAAAGT ΑΑΤ GGTGGT AGCACC
`Τ ACT AT CC AG ACACT GT G AAGG ACCG ATT C ACCATTT CCAG AG ACAATGCC AAG AAC AC
`CCT GT ACCT GC ΑΑΑΤ G AGCAGT CTG AGG CCT G AGG AC AC AGCCTT GT ATT ACT GTGCA
`CATGGT CT CCT GTTT GCT CACT GGGGCCAAGGGACT CT GGT CACT GT CT CTGCA (SEQ
`ID ΝΟ:92)
`
`FIG. 22Β
`
`Lassen - Exhibit 1011, p. 45
`
`
`
`Patent Application Publication
`
`Jul. 5, 2018 Sheet 45 of 61
`
`US 2018/0186872 Α1
`
`BSO-5E5
`
`G ATGT ACAGGTT C AGG AGT CAGG ACCT GGCCTCGT G AAACCTT CT C AGT CTCTGTCTCT
`CACCT G CTCTGT C ACT GGCTACT CC AT C ACC AGT GATT ATT ACT GG AACT GG AT CCGGC
`AGTTTCCAGG AAACAAACT GG AATGG ATGGGCT ACAT AAGCT ACGAT AGT AGCAAT AAC
`Τ AC AACCC AT CT CT C AAA ΑΑΤ CG ΑΑΤ CTCC AT C ACT CGT G ACACAT CT AAGAACCAGTTT
`IT CCTG AAGTT G ΑΑΤΤ CT GIG ACT ACT GAGGACAC AGCCACAT ATT ACT GT GCTT CAGT
`GGGTT ATT ACT ACGTT AGTGACT GGT ACTT CGATGT CT GGGGCACAGGG ACC ACGNT C
`ACCGTCTCCTCA (SEQ ID ΝΟ:93)
`
`BSO-7G9
`
`CAGGTCCAACTGCAGCAGCCTGGGGCT G AGCTGGT AAAGCCT GGGGCTT CAGT GAGG
`TTGTCCTGCAAGGCTT CTGGCT ACACTTT CACCAGCT ACT GG AT GCACT GGGTG AAGCA
`GAGGCCT GG ACAAGGCCTT G AGTGGATT GGAAT G ATTC AT CCT ΑΑΤ AGT GGTT AT ACT A
`ATT ACAAT G AG AAGTTCAAG AT CAAGGCCACACTG ACTGT AG AC ΑΑΑΤ CCT CC AGCACA
`GCCCACAT GC AACT CAGCAGCCT G ACAT CT GAGG ATT CT GCGGT CT AT CACT GT GCAA
`G AGGGGGGT AT GAT GGTT CCT ACGGGCCCT GGTTT GCTT ACT GGGGCCAAGGG ACT C
`TGGTCACTGTCTCTGCA (SEQ ID ΝΟ:94)
`
`BSO-9A7
`
`CAGGTCCAACTGCAGCAGCCTGGGGCTGAGCTGGTGAGGCCTGGGTCTTCAGTGAAG
`CTGTCCTGCAAGGCTTCTGGCTACACCTTCACCAACTACTGGATGCATTGGTTGAAGCA
`GAGGCCT GTACAAGGCCTT G AGTGG ATTGGT AAC ATT GGCCCTT CT GAT AGT AAAACT C
`ACT ACAATCAAAAATTCAAGGACAAGGCCACATTGACTGTAGACAAAT CCT CCAGCACA
`GCCT ACATGCAACT CAACAGCCT GACAT CTG AGG ACTCT GCGGT CT ATT ACT GTGC AAG
`GGGT GATT ACGTCCTGTTT ACTT ACTGGGGCCAAGGGACTCT GGT CACT GT CT CTGCA
`(SEQ ID ΝΟ:95)
`
`BSO-1QD11
`
`CAGGTCCAGCTGCAGCAGTCTGGAACTGAGCTGGTAAGGCCTGGGACTTCAGTGAAGA
`TGTCCTGCAAGGCTGCTGGATACACCTTCACTGACTACTGGATAGGTTGGATAAAGCAG
`AGGCCT GG ACAT GGCCTT G AGTGG ATTGG AG AT ΑΤΤΤΤ CCCT GG AGGTG ATT AT ACT ΑΑ
`GTGCAGT GAGAGGTT CAAGGGCAAGGCCAAACT GACTGCAGACACAT CCT CCAGCACT
`GCCT ACAT GC AGCT C AGCAG ACT GACAT CT GAGG ACT CT GCC AT CT ATT ACT GT G C AAG
`AAGG AGT ACT ACGAT ACGCTT CGGGGCT ATGGACAACTGGGGT CAAGGAACCTCAGT C
`ACCGTCTCCTCA (SEQ ID ΝΟ:96)
`
`FIG. 22Β (Cont.)
`
`Lassen - Exhibit 1011, p. 46
`
`
`
`Patent Application Publication
`
`Jul. 5, 2018 Sheet 46 of 61
`
`US 2018/0186872 Α1
`
`BSQ-13B10
`
`C AGGT GCAGCT G AAGG AGT CAGG ACCT GGCCTGGT GGCGCCCT CACAGAGCCT GTCC
`AT C ACAT GC ACT GT CT CT GGGTT CT C ATT A ACC AGCTTTT CT AT AAGCT GGGTT CGCC A
`GCCACCAGGAAAGGGTCTGGAGTGGCTTGGAGGAATATGGACTGGTGGAGGCACAAA
`ΤΤ AT AATTCAGCT CTCAAACCCAGACT GAGCAT CAGCAAAGACAACT CCA AG AGT CAAG
`ΤΠΤ CTT AAAAATG AACAGT CTGCAAACT G ATG AC AC AGCCAGGT ACT ACT GTGCCAG A
`ΑΑΤ AGTAACT ACCCTT CCGGGTTTGCTT ACT GGGGCCAAGGGACT CT GGT CACT GT CT C
`TGCA (SEQ ID ΝΟ:97)
`
`FIG. 22Β (Cont.)
`
`Lassen - Exhibit 1011, p. 47
`
`
`
`Patent Application Publication Jul. 5, 2018 Sheet 47 of 61 US 2018/0186872 Α1
`
`iD
`RA1
`RA2
`RA3
`RA4
`RA5
`RA6
`RA7
`RA8
`RA9
`RA10
`RA11
`RA12
`RA13
`RA14
`RA15
`RA16
`RA17
`
`Clone
`BSO-1E3
`BSO-2C1
`BSO-2E5
`BSO-4G3
`BSO-5E5
`BSO-7G9
`BSO-9A7
`BSO-10D11
`BSO-13B10
`BSW-1D3
`BSW-1F6
`BSW-4G5
`BSW-6H3
`BSW-7E9
`BSW-7G8
`BSW-7H8
`BSW-8B7
`
`FIG. 23
`
`Mouse IL11RA ab$ m human atrial fibroblasts
`I Unstimufated: 1
`
`industry
`standard;.
`
`Stimulated* 1.58
`
`JK K\ .¾ A> *a> rt<h Jh
`Qs' W W V V V V V %■ <V <V
`βΒΜΑ+ eels (norm,)
`
`FIG. 24
`
`Lassen - Exhibit 1011, p. 48
`
`
`
`Patent Application Publication Jul. 5, 2018 Sheet 48 of 61 US 2018/0186872 Α1
`
`FIG. 25
`
`Mouse IL11RA abs on human atrial fibroblasts
`stimulated with 111 1:111 1RA
`
`Industry standard; 1,32
`Unstimulated: 1
`
`Stimulated: 2.34
`
`<o -Λ Oj . Ν *h .<3 .Λ .O Jh .¾
`O' <5* Qr ν ν ν ν ν %■ %■
`ΜΜΡ2 (norm,)
`
`FIG. 26
`
`Number of Antibodies
`
`Number of Antibodies
`
`Lassen - Exhibit 1011, p. 49
`
`
`
`Patent Application Publication Jul. 5, 2018 Sheet 49 of 61 US 2018/0186872 Α1
`
`Antibody
`Candidate
`Unstimuiated
`Stimulated
`industry Standard
`RAt
`...........RA2........
`RA3
`RA4
`RA1
`RA6
`RA7
`RA8
`ΑΑζ
`RAID
`RA11
`RA12
`RA13
`RA14
`RA15
`RA16
`RA17
`
`Human !L11
`activated fibrabiasts {norm.)
`
`Mouse IL11
`activated fttarobteste {norm.}
`
`Trans iL11
`ΜΜΡ2 {norm.}
`
`5.58
`
`2 03
`' SO
`2»
`* sc:
`
`2.28
`***C
`
`FIG. 27
`
`....ν.ν.ν.....;:. .•••**■
`
`0 9ΗΗΗΗΗΗΒΚ
`& :l^llll:l;llll:lll:illlllllllllll;i
`
`FIG. 28Α
`
`Lassen - Exhibit 1011, p. 50
`
`
`
`Patent Application Publication Jul. 5, 2018 Sheet 50 of 61 US 2018/0186872 Α1
`
`FIG. 28Β
`
`aSMA*
`
`FIG. 29Α
`
`Lassen - Exhibit 1011, p. 51
`
`
`
`Patent Application Publication
`
`Jul. 5, 2018 Sheet 51 of 61 US 2018/0186872 Α1
`
`BM*
`
`FIG. 29C
`
`Lassen - Exhibit 1011, p. 52
`
`
`
`Patent Application Publication
`
`Jul. 5, 2018 Sheet 52 of 61 US 2018/0186872 Α1
`
`FIG. 29D
`
`FIG. 30
`
`Lassen - Exhibit 1011, p. 53
`
`
`
`Patent Application Publication Jul. 5, 2018 Sheet 53 of 61 US 2018/0186872 Α1
`
`ο
`
`cod
`
`UL
`
`
`
` mοrmQ
`
`si
`m F
`
`IG. 32Α
`
`Lassen - Exhibit 1011, p. 54
`
`
`
`Patent Application Publication Jul. 5, 2018 Sheet 54 of 61 US 2018/0186872 Α1
`
`Lassen - Exhibit 1011, p. 55
`
`
`
`Patent Application Publication Jul. 5, 2018 Sheet 55 of 61
`
`US 2018/0186872 Α1
`
`No
`
`Clone
`
`2
`3
`4
`5
`6
`7
`8
`9
`
`BSO-2C1
`BSO-2E5
`8SO-4G3
`8SO-5E5
`8SO-7G9
`BSO-9A7
`BSO-10D11
`BSQ-13B1G
`positive control
`negative
`control
`
`incubated on
`cells transfected with
`pB1-IL11-hiim.FL
`flow cytometry (Attunes)
`Results of suheloning
`GMrj
`% positive
`
`140%
`30%
`30%
`23%
`59%
`111%
`42℅
`35%
`100%
`
`3%
`
`44127
`9545
`9302
`S7S0
`18649
`34771
`1313S
`10931
`31429
`
`930
`
`FIG. 34Α
`
`Ssofype
`
`!gG1/kappa
`igG2b/kappa
`lgG1/kappa
`igG1/lgG2b/kappa
`JgG2a&2c /kappa
`lgG1/kappa
`lgG1/kappa
`igG1/kappa
`
`160%
`
`140%.
`
`120%
`
`100%
`
`80%
`
`60%
`
`40%
`
`20%
`
`0%
`
`123450789
`
`FIG. 34Β
`
`Lassen - Exhibit 1011, p. 56
`
`
`
`Patent Application Publication Jul. 5, 2018 Sheet 56 of 61 US 2018/0186872 Α1
`
`Lassen - Exhibit 1011, p. 57
`
`
`
`Patent Application Publication Jul. 5, 2018 Sheet 57 of 61 US 2018/0186872 Α1
`
`Collagen Histology
`
`FIG. 35Β
`
`Urine Albumin/creatinine ratio
`
`FIG. 36
`
`Lassen - Exhibit 1011, p. 58
`
`
`
`Patent Application Publication
`
`Jul. 5, 2018 Sheet 58 of 61 US 2018/0186872 Α1
`
`sham
`
`UUO igG
`
`UUO 111 1 RA
`
`FIG. 37A
`
`FIG. 37Β
`
`Lassen - Exhibit 1011, p. 59
`
`
`
`Patent Application Publication Jul. 5, 2018 Sheet 59 of 61 US 2018/0186872 Α1
`
`Human liver samples
`au>
`nc
`
`mi
`
`hash
`
`FIG. 38
`
`IL-11
`
`Rost Control Control Control Combo Combo
`wltf»S
`wMLKB
`
`FIG. 39
`
`1000
`im
`
`m1
`
`00
`
`00
`
`0
`
`Ε ma
`
`Lassen - Exhibit 1011, p. 60
`
`
`
`Patent Application Publication Jul. 5, 2018 Sheet 60 of 61 US 2018/0186872 Α1
`
`Perivascular
`
`FIG. 40Α
`Perivascular
`
`Perivascular
`
`endocardium
`
`gpiearsfem
`
`endocardium
`
`gpteardsum
`
`endocardium
`
`Epimrtimm
`
`lAminmm
`
`mc+igcs
`
`SHAW
`
`Lassen - Exhibit 1011, p. 61
`
`
`
`Patent Application Publication Jul. 5, 2018 Sheet 61 of 61 US 2018/0186872 Α1
`
`SHAH
`
`TA€+igG
`
`w^wwwwwwwwwwwwwwwywwwwwwwwwwwwwwwwwvt
`
`1
`
`WWWWWWWWWWWWWWWWWWSyWWWWWWWWWWWWWWWWW>»
`
`TAOIL11RA Ai>
`
`FIG. 40Β
`
`<»
`
`m -.-
`
`-.-.-
`
`..-
`
`A.-.
`-.-
`
`--j—
`
`Col lagan par flsssta mass (jig/mg)
`
`Lassen - Exhibit 1011, p. 62
`
`A
`
`
`US 2018/0186872 Α1
`
`1
`
`Jul. 5,2018
`
`IL-11RA ANTIBODIES
`
`-continued
`
`CROSS-REFERENCE TO RELATED
`APPLICATIONS
`
`[0001] The present application claims priority under 35
`USC § 119(a)-(d) to United Kingdom Application No.
`1621439.7, filed Dec. 16, 2016, the entire contents of which
`are incorporated by reference herein.
`
`FIELD OF THE INVENTION
`
`[0002] The present invention relates to antibodies that
`bind to interleukin 11 Receptor alpha (IL-llRa).
`
`BACKGROUND TO THE INVENTION
`
`[0003] Many fatal and incurable diseases are caused by
`organ failure due to excessive and maladaptive fibrosis
`(Rockey et al., 2015 Journal of Infectious Diseases 214,
`jiwl76). Fibrotic disorders include both rare, genetically-
`driven diseases such as scleroderma, idiopathic pulmonary
`fibrosis and hypertrophic cardiomyopathy, dilated cardio
`myopathy (DCM), and common disea
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