Discovery and Characterization of a High Potency Anti-Inflammatory Trispecific TNFα/IL-17A/IL-17F Inhibitor

APRIL 29, 2016 PEGS, BOSTON

DISCOVERY AND CHARACTERIZATION OF A HIGH POTENCY ANTI-INFLAMMATORY

TRISPECIFIC TNF⍺/IL-17A/IL-17F INHIBITOR

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



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


YEAR 2012


YEAR 2012

SAINT-PETERSBURG


YEAR 2012

SAINT-PETERSBURG MOSCOW


YEAR 2012


PHAGE DISPLAY


YEAR 2012


PHAGE DISPLAY 454 SEQUENCING SYSTEMS


YEAR 2012


PHAGE DISPLAY 454 SEQUENCING SYSTEMS

IL17A


454 SEQUENCING SYSTEMS


ANTIBODY ANNOTATION

V/D/J GENESFR/CDR

SOMATIC MUTATIONS

GERMLINE FAMILIES


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

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

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


ALIGNMENT-BASED ANNOTATION

5’ V

3’ J



5’ V

3’ J3’ J

3’ J



5’ V

3’ J

3’ J 3’ J

3’ J3’ J

5’ V 5’ V


STRANGE SEQUENCES


STRANGE SEQUENCES

VH3 family


STRANGE SEQUENCES

VH3 family

Unnormal FR2


STRANGE SEQUENCES

VH3 family

Unnormal FR2

Some unusual mutations in FR3


STRANGE SEQUENCES

VH3 family

Unnormal FR2

Some unusual mutations in FR3

Enlarged CDR3


VHH


LEAD OPTIMIZATION PLAN

Make a classic Fv

Humanize heavy chain


PAIRING VHH

VLVH


HUMANIZATION


HUMANIZATION


HUMANIZATION


HUMANIZATION

AFFINITY MATURATION

Δ Affinity


BCD 085

ANTI-IL17

Development Preclinical Studies I Phase II Phase III Phase Registration ✓


AUTOMATIC PIPELINE


ANTI-TNF⍺

TNF⍺

VH

VL


CONSTRUCTION OF TRISPECIFIC






BACK TO VHH

VL VH


BACK TO VHH

VL VH


BACK TO VHH

45T

44G


BCD 085 VHH

VHH

IL17a


BCD 121

CH

VH

CL

VL

VHH


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Health & Medicine

Discovery and Characterization of a High Potency Anti-Inflammatory Trispecific TNFα/IL-17A/IL-17F Inhibitor