discovery and characterization of a high potency anti-inflammatory trispecific tnfα/il-17a/il-17f...
TRANSCRIPT
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APRIL 29, 2016 PEGS, BOSTON
DISCOVERY AND CHARACTERIZATION OF A HIGH POTENCY ANTI-INFLAMMATORY
TRISPECIFIC TNF⍺/IL-17A/IL-17F INHIBITOR
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AUTHORSS. AGEEV A. ULITIN E. ZUBAREVA I. USTUGOV D. KORZHAVIN E. LOMKOVA V. SOLOVJEV E. SOFRONOVA V. EKIMOVA
A. ALEXANDROV A. KARABELSKY Y. BASOVSKIY V. USATOVA T. CHERNOVSKAYA E. MOROZOVA A. GRACHEV R. IVANOV D. MOROZOV
PRESENTER:
PAVEL YAKOVLEV
APRIL 29, 2016 PEGS, BOSTON
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APRIL 29, 2016 PEGS, BOSTON
BCD 121
OctetRED96 measurement demonstrated that BCD 121
is capable to simultaneous non-completitive IL-17A
and TNF ligand binding.
Blue lines — added 1 mkg/ml TNFa
Red and green — without TNFa
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APRIL 29, 2016 PEGS, BOSTON
YEAR 2012
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APRIL 29, 2016 PEGS, BOSTON
YEAR 2012
SAINT-PETERSBURG
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APRIL 29, 2016 PEGS, BOSTON
YEAR 2012
SAINT-PETERSBURG MOSCOW
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APRIL 29, 2016 PEGS, BOSTON
YEAR 2012
SAINT-PETERSBURG MOSCOW
PHAGE DISPLAY
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APRIL 29, 2016 PEGS, BOSTON
YEAR 2012
SAINT-PETERSBURG MOSCOW
PHAGE DISPLAY 454 SEQUENCING SYSTEMS
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APRIL 29, 2016 PEGS, BOSTON
YEAR 2012
SAINT-PETERSBURG MOSCOW
PHAGE DISPLAY 454 SEQUENCING SYSTEMS
IL17A
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APRIL 29, 2016 PEGS, BOSTON
454 SEQUENCING SYSTEMS
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APRIL 29, 2016 PEGS, BOSTON
ANTIBODY ANNOTATION
V/D/J GENESFR/CDR
SOMATIC MUTATIONS
GERMLINE FAMILIES
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APRIL 29, 2016 PEGS, BOSTON
PATTERN MINING
FR1 CDR1 FR2 CDR2 FR3QVQLVQSGAEVKKPGASVKVSCKASGYTFT G--YYMH WVRQAPGQGLEWMG WINP--NSGGTNYAQKFQG RVTMTRDTSISTAYMELSRLRSDDTAVYYCARQVQLVQSGAEVKKPGASVKVSCKASGYTFT S--YAMH WVRQAPGQRLEWMG WINA--GNGNTKYSQKFQG RVTITRDTSASTAYMELSSLRSEDTAVYYCARQVQLVQSGAEVKKPGASVKVSCKASGYTFT S--YDIN WVRQATGQGLEWMG WMNP--NSGNTGYAQKFQG RVTMTRNTSISTAYMELSSLRSEDTAVYYCARQVQLVQSGAEVKKPGASVKVSCKASGYTFT S--YGIS WVRQAPGQGLEWMG WISA--YNGNTNYAQKLQG RVTMTTDTSTSTAYMELRSLRSDDTAVYYCARQVQLVQSGAEVKKPGASVKVSCKVSGYTLT E--LSMH WVRQAPGKGLEWMG GFDP--EDGETIYAQKFQG RVTMTEDTSTDTAYMELSSLRSEDTAVYYCATQMQLVQSGAEVKKTGSSVKVSCKASGYTFT Y--RYLH WVRQAPGQALEWMG WITP--FNGNTNYAQKFQD RVTITRDRSMSTAYMELSSLRSEDTAMYYCARQVQLVQSGAEVKKPGASVKVSCKASGYTFT S--YYMH WVRQAPGQGLEWMG IINP--SGGSTSYAQKFQG RVTMTRDTSTSTVYMELSSLRSEDTAVYYCARQMQLVQSGPEVKKPGTSVKVSCKASGFTFT S--SAVQ WVRQARGQRLEWIG WIVV--GSGNTNYAQKFQE RVTITRDMSTSTAYMELSSLRSEDTAVYYCAAQVQLVQSGAEVKKPGSSVKVSCKASGGTFS S--YAIS WVRQAPGQGLEWMG GIIP--IFGTANYAQKFQG RVTITADESTSTAYMELSSLRSEDTAVYYCARQVQLVQSGAEVKKPGSSVKVSCKASGGTFS S--YAIS WVRQAPGQGLEWMG GIIP--IFGTANYAQKFQG RVTITADKSTSTAYMELSSLRSEDTAVYYCAREVQLVQSGAEVKKPGATVKISCKVSGYTFT D--YYMH WVQQAPGKGLEWMG LVDP--EDGETIYAEKFQG RVTITADTSTDTAYMELSSLRSEDTAVYYCATQITLKESGPTLVKPTQTLTLTCTFSGFSLS TSGVGVG WIRQPPGKALEWLA LIY---WNDDKRYSPSLKS RLTITKDTSKNQVVLTMTNMDPVDTATYYCAHRQVTLKESGPVLVKPTETLTLTCTVSGFSLS NARMGVS WIRQPPGKALEWLA HIF---SNDEKSYSTSLKS RLTISKDTSKSQVVLTMTNMDPVDTATYYCARIQVTLKESGPALVKPTQTLTLTCTFSGFSLS TSGMRVS WIRQPPGKALEWLA RID---WDDDKFYSTSLKT RLTISKDTSKNQVVLTMTNMDPVDTATYYCARIEVQLVESGGGLVQPGGSLRLSCAASGFTFS S--YWMS WVRQAPGKGLEWVA NIKQ--DGSEKYYVDSVKG RFTISRDNAKNSLYLQMNSLRAEDTAVYYCAREVQLVESGGGLVQPGRSLRLSCAASGFTFD D--YAMH WVRQAPGKGLEWVS GISW--NSGSIGYADSVKG RFTISRDNAKNSLYLQMNSLRAEDTALYYCAKDQVQLVESGGGLVKPGGSLRLSCAASGFTFS D--YYMS WIRQAPGKGLEWVS YISS--SGSTIYYADSVKG RFTISRDNAKNSLYLQMNSLRAEDTAVYYCAREVQLVESGGGLVQPGGSLRLSCAASGFTFS S--YDMH WVRQATGKGLEWVS AIG---TAGDTYYPGSVKG RFTISRENAKNSLYLQMNSLRAGDTAVYYCAREVQLVESGGGLVKPGGSLRLSCAASGFTFS N--AWMS WVRQAPGKGLEWVG RIKSKTDGGTTDYAAPVKG RFTISRDDSKNTLYLQMNSLKTEDTAVYYCTTEVQLVESGGGVVRPGGSLRLSCAASGFTFD D--YGMS WVRQAPGKGLEWVS GINW--NGGSTGYADSVKG RFTISRDNAKNSLYLQMNSLRAEDTALYHCAREVQLVESGGGLVKPGGSLRLSCAASGFTFS S--YSMN WVRQAPGKGLEWVS SISS--SSSYIYYADSVKG RFTISRDNAKNSLYLQMNSLRAEDTAVYYCAREVQLLESGGGLVQPGGSLRLSCAASGFTFS S--YAMS WVRQAPGKGLEWVS AISG--SGGSTYYADSVKG RFTISRDNSKNTLYLQMNSLRAEDTAVYYCAK
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PATTERN MATCHING
S
S
S AM
S
A
S
V T Y
Y
A
A A
S
V
Q
S
Y
T
S S
P
GS Y
R
RV
Y
L
E
I
L
P
DF
A
F
G
S
AA
C
S
W
V
R
QS
V
W
R
F
T
A
C
Y
Y
W
G
Q
A
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PATTERN MATCHING
S
S
F PM
G
G
G
G A H
Y
E
N D
F
V
K
W
N
I
G G
F
SY S
G
TD
Y
R
Y
G
T
DF
T
L
W
F
R
QA
V
F
R
F
A
A
C
Y
Y
W
G
Q
T
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APRIL 29, 2016 PEGS, BOSTON
ALIGNMENT-BASED ANNOTATION
5’ V
3’ J
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APRIL 29, 2016 PEGS, BOSTON
ALIGNMENT-BASED ANNOTATION
5’ V
3’ J3’ J
3’ J
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APRIL 29, 2016 PEGS, BOSTON
ALIGNMENT-BASED ANNOTATION
5’ V
3’ J
3’ J 3’ J
3’ J3’ J
5’ V 5’ V
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APRIL 29, 2016 PEGS, BOSTON
STRANGE SEQUENCES
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APRIL 29, 2016 PEGS, BOSTON
STRANGE SEQUENCES
VH3 family
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APRIL 29, 2016 PEGS, BOSTON
STRANGE SEQUENCES
VH3 family
Unnormal FR2
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APRIL 29, 2016 PEGS, BOSTON
STRANGE SEQUENCES
VH3 family
Unnormal FR2
Some unusual mutations in FR3
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APRIL 29, 2016 PEGS, BOSTON
STRANGE SEQUENCES
VH3 family
Unnormal FR2
Some unusual mutations in FR3
Enlarged CDR3
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APRIL 29, 2016 PEGS, BOSTON
VHH
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APRIL 29, 2016 PEGS, BOSTON
LEAD OPTIMIZATION PLAN
Make a classic Fv
Humanize heavy chain
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APRIL 29, 2016 PEGS, BOSTON
PAIRING VHH
VLVH
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APRIL 29, 2016 PEGS, BOSTON
HUMANIZATION
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APRIL 29, 2016 PEGS, BOSTON
HUMANIZATION
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APRIL 29, 2016 PEGS, BOSTON
HUMANIZATION
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APRIL 29, 2016 PEGS, BOSTON
HUMANIZATION
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AFFINITY MATURATION
Δ Affinity
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APRIL 29, 2016 PEGS, BOSTON
BCD 085
ANTI-IL17
Development Preclinical Studies I Phase II Phase III Phase Registration ✓
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APRIL 29, 2016 PEGS, BOSTON
AUTOMATIC PIPELINE
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APRIL 29, 2016 PEGS, BOSTON
ANTI-TNF⍺
TNF⍺
VH
VL
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APRIL 29, 2016 PEGS, BOSTON
CONSTRUCTION OF TRISPECIFIC
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APRIL 29, 2016 PEGS, BOSTON
CONSTRUCTION OF TRISPECIFIC
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APRIL 29, 2016 PEGS, BOSTON
CONSTRUCTION OF TRISPECIFIC
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APRIL 29, 2016 PEGS, BOSTON
BACK TO VHH
VL VH
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APRIL 29, 2016 PEGS, BOSTON
BACK TO VHH
VL VH
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APRIL 29, 2016 PEGS, BOSTON
BACK TO VHH
45T
44G
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APRIL 29, 2016 PEGS, BOSTON
BCD 085 VHH
VHH
IL17a
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APRIL 29, 2016 PEGS, BOSTON
BCD 121
CH
VH
CL
VL
VHH