Glenmark, an Indian Pharmaceutical Company in Switzerland ... IMPROVER NVC... · Glenmark, an Indian Pharmaceutical Company in Switzerland – Innovation with a touch of spice Sam

Glenmark an Indian Pharmaceutical Company in Switzerland ndash Innovation

with a touch of spice

Sam Hou

Head Biologics Research Glenmark Pharmaceuticals SA

Mar 2014

1

bull Intro ndash Glenmark GBR 910 anti ndashTL1A antibody GBR830 anti-OX40 antibody BEAT bispecific antibody

2

Glenmark Pharmaceuticals - a research driven global integrated pharmaceutical company

bull Drug discovery business oriented towards out-licencing at various clinical stages

bull Branded generics business with a global presence

(EU US and across emerging markets including India)

3

Glenmark Pharmaceuticals

Turnover $32 MN 2 Formulations Manufacturing Facilities

Operations in 27 countries

Sales from International operations 8

Initiation into NCE research

2000

Turnover (FY 2012) $919 MN (+24)

12 Mfg Facilities over 4 Countries

Operations gt 95 Countries gt9000 employees

Sales from international operations gt70

Strong Pipeline of NCErsquos and NBErsquos

2013

API Mfg

Pure Generics Business

Branded Generics business

Proprietary Branded Business

O P E R A T I O N S A C R O S S T H E P H A R M A C E U T I C A L V A L U E C H A I N

4

Global Footprint

5

RampD for Biologics

Switzerland

Glenmark

Generics Ltd US

Glenmark

Generics SA

Argentina

Medicamenta

Czech Republic

Glenmark

Farmacetica Ltda

Brazil

Glenmark Pharma

Europe Limited

London UK

Bowter Bartlett

South Arica

Glenmark

India

Several other subsidiaries and representative offices exist across the world

Discovery Research Centres

350 Scientists based in Mumbai India Around 50 scientists based in Switzerland

6 Discovery

Candidates in

Clinical Trials

NCE Research NBE Research

Around USD 200 Million received from out-licensing deals of NCErsquos and NBErsquos

6

Novel Drugs Pipeline Compound Primary Indications Target

Pre Clinicals Phasel Phase2 Phase3 Approval

HIV related Diarrhea CFTR Inhibitor

Adult Acute Infectious Diarrhea including Cholera

CFTR Inhibitor

Neuropathic Pain TRP A1 Inhibitor

Respiratory disorders TRP A1 Inhibitor

GRC 15300 Neuropathic Pain TRPV3 Antagonist

mPGES-1 inhibitors

Chronic Inflammatory conditions including Pain

mPGES-1 inhibitors

Vatelizumab Ulcerative Colitis VLA-2 Antagonist (mAb)

GBR 900 Chronic Pain TrkA Antagonists (mAb)

GBR 830 Autoimmune Disorders OX 40 Antagonist (mAb)

Out-licensed to Sanofi

In-licensed for ROW Markets

Option agreement with Forest Laboratories


NCE

NBE

Crofelemer

GRC 17536


7

Glenmark in Switzerland Glenmark Pharmaceutical Ltd (India) set up a wholly owned subsidiary Glenmark Pharmaceuticals

SA in Switzerland in July 2004

Biologics Research Lab established in 2006

Process Development established in 2008

GMP Manufacturing established in 2014

Team of 60 (Scientists ~ 50) focusing on developing monoclonal antibodies against inflammation and oncology disease areas

International team of highly qualified scientists with biopharmaceutical research experience Collaborations with numerous biologic companies amp leading academic institutions

8

RampD Biologics

Antibody Drug Discovery

Aspirin

Cyclosporine

9

Glenmarkrsquos GBR 910 TL1A Antagonist Program

10

TL1A (TNFSF15)

bull(discovered in 2002) is a member of the TNF ligand superfamily which comprises 18

different members in mammals

bull Type II transmembrane proteins homotrimeric Cleavable

- TL1A expression on

bullActivated Antigen-Presenting Cells (DC and macrophages)

bullActivated CD4+ and CD8+ T lymphocytes

bullTNFαIL-1 α activated endothelial cells

bull Binds to DR3 (death receptor 3 TNFRSF25 TRAMP LARD WSL-1) and DcR3 (decoy

receptor)

Migone 2002 Immunity 16 479-492

1-35 cytoplasmic 36-56 TM 57-251 extracellular

N C

11

Biologics targeting TNF family members

12

TL1A linking innate and adaptive immunity

X

X

X

13


14 Meylan Immuno Rev 2011

TL1A

Rheumatoid arthritis IBD

Asthma

Multiple sclerosis

(EAE)

Psoriasis

Potential role for TL1A the new TNF-family member and potent costimulator of IFN-gamma in mucosal inflammation

Prehn JL Mehdizadeh S Landers CJ Luo X Cha SC Wei P Targan SR

Expression Localization and Functional Activity of TL1A a Novel Th1-Polarizing Cytokine in Inflammatory Bowel Disease 1

Giorgos Bamias Charles Martin III Marco Marini Sharon Hoang Margarita Mishina William G Ross Muhammadreza A Sachedina Charles M

Friel

Role of TL1A in the Pathogenesis of Rheumatoid Arthritis1

Jun Zhang234Dagger Xuehai Wang2 Hassan Fahmi Susan WojcikDagger James FikesDagger Youhua Yusect Jiangping Wudagger and Hongyu Luo

Upregulation and nuclear localization of TNF-like cytokine 1A (TL1A) and its receptors DR3 and DcR3 in psoriatic skin lesions

Bamias G Evangelou K Vergou T Tsimaratou K Kaltsa G Antoniou C Kotsinas A Kim S Gorgoulis V Stratigos AJ Sfikakis PP

Essential role of TNF receptor superfamily25 (TNFRSF25) in the development of allergic lung inflammation (JEM 2008)

Lei Fang Becky Adkins Vadim Deyev and Eckhard R Podack

Selected

References

COPD

TL1ADR3 axis in inflammation and autoimmune diseases

atherosclerosis

15

bull TL1A-DR3 in health and disease

ndash High TL1A expression in synovial tissue of RA patients (membrane bound and soluble)

(Cassatella JI 2007 Bamias Clin Imm 2008Zhang JI 2009)

ndash High TL1A and DR3 expression in intestinal lamina propria of IBD patients (Bamias JI 2003Prehn Clin Imm 2004Kamada Inlamm

Bowel Dis 2009)

bull Mouse model of IBD (Takedatsu Gastroentero 2008)

16

TL1A in allergic lung inflammation (Fang JEM 2008)

Same observations were made in DR3-- animals (Meylan Immunity 2008)

0 5 12

-1 0 +1 +2 +3 +4

16

Ova+alum (ip) Ova+alum (ip) Ova (aero) Ab Ab Ab Ab Analysis

L4G6 blocking hamster anti-mouse TL1A mAb BALF Bronchoalveolar lavage fluid

mucus

In vitro stimulation of bronchial LN

Cytokine expression on lung parenchyma

Ab 50ug ip

Ab injected 4 hours before analysis

17

Induction of TL1A expression in a mouse model of IBD

F480

F480

TL

1A

T

L1

A Naive mouse

Mouse with UC

UC= Ulcerative colitis

18

Induction of TL1A expression in a mouse model of Allergic Asthma

Siglec F PE

CD

11c

AP

C

Siglec F-PE

Alveolar macrophages

Eosinophils

Isotype control on alveolar macrophages

TL1A on steady state alveolar macrophages

TL1A on asthmatic state alveolar macrophages

BAL of OVA-induced allergic asthma mouse

19

GBR910 blocks TL1A-induced IFN-γ secretion by primed CD4 T cells

IL-12 + IL18 - + + + + + +

IC monocytes - - + + + + +

5G6 (μgml) - - - 10 1 01 -

Isotype control - - - - - - +

Parental 5G6 candidate blocks

IFNg release induced by membrane bound TL1A

(produced by IC-activated monocytes)

IC Monocyte

Mb TL1A

T cell

DR3

IFNg

IFNg

IFNg

IFNg

IFNg

IFNg

IFNg

Humanized 5G6 blocks IFNγ release induced

by soluble recombinant hTL1A

soluble TL1A

T cell

DR3

IFNg

IFNg

IFNg

IFNg

IFNg

IFNg

IFNg

20

Number of eosinophils in BAL fluids

Contr

ol iso

Dex

amet

hasone

GBR91

0 (5

0mgk

g)

Nai

ve

00

2000000

4000000

6000000

8000000

nu

mb

er

of

eo

sin

op

hil

s

Her

ceptin

(20m

gkg)

Cyc

losp

orin

5G6

(20m

gkg)

No

DSS

5

6

7

8

colo

n l

eng

th (

cm

)

IBD and Allergic Asthma models

DSS colitis

OVA-induced asthma

21

Day -1

Termination of the study

- Adhesion

- Strictures

- Ulcers

- Wall thickness

- HampE

- PAS

N=8

(rats Sprague Dawley)

Body weight

Day 0

Group1 Isotype control without TNBS

Group2 Isotype control+TNBS

Group3 GBR910

Group4 Prednisolone

starvation

+2 hours Day 7

treatment

Colon length

Histology

GBR910 in rat TNBS colitis model

22

00

05

10

15

20

25

30

35

Adhesions Strictures Ulcers score Thicknessscore

AV

ER

AG

E C

OLO

NIC

SC

OR

E

COLONIC PARAMETER

-TNBS +TNBS GBR910 prednisolone

plt005 by Students t-test

GBR910 ameliorates TNBS-induced inflamation in rat

23

Summary Key attributes of GBR 910 and outlook

GBR 910 humanized mAb in IgG4HS backbone (blocker only)

Binding activity GBR 910 is cross-reactive with cyno sheep rat mouse

In vitro activity

- GBR 910 blocks binding of TL1A to DR3

-GBR 910 neutralizes IFNg-mediated T cell responses in vitro

In vivo GBR 910 ameliorates TNBS-induced inflammation in a rat model of Crohnrsquos disease (TNBS colitis)

Good anticipated safety profile Very narrow expression pattern

Envisaged other models of inflammatory disease in rat

COPD Chronic IBD models

24

Glenmarkrsquos GBR 830 OX40 Antagonist Program

25

OX 40 Target Characteristics Advantages in Targeting OX40

bull Co-stimulatory Receptor on T-cells tumor necrosis factor receptor superfamily member

bull Not found on naiumlve T-cells or memory T-cells transiently induced during T-cell activation

bull Specific for recently activated T-cells ndash No pan-immunosuppression

ndash Fewer severe infections and malignancies than small molecule and mAb immunosuppressants

26

OX40-OX40L Signalling in T-Cell Activation

27

OX40L (active homo-trimer)

OX40 (active homo-

trimer)

Antigen Presenting Cell

Activated T-Cell

- OX40 co-stimulation only on activated T-cells after initial T-cell activation through CD28 - OX40-OX40L co-stimulation is a required step during clonal T-cell expansion and during memory cell reactivation

Survival Proliferation

Effector function Differentiation

OX40 signals OX40 signals

C D28 signals

memory memory

Naive

Effector

Expansion Contraction

Memory generation

Reactivation effector

OX40-OX40L Signalling Disruption in T-Cell Activation

28


OX40 (active homo-

trimer)


Activated T-Cell

- Disruption of OX40-OX40L interaction disturbs T-cell proliferation survival effector function and differentiation The net result is

- Weaker and shorter effector phase - Impaired memory generation and reactivation

- Early expansion of naiumlve T-cells not affected (allows limited T-cell effector function) innate immune responses are not affected by targeting OX40



Smaller memory pool

Contraction sooner

Smaller effector Weaker late expansion

Weaker reactivation

Early expansion normal

memory memory Naive

effector

The OX40-OX40L Axis is well validated in Animal Models of Inflammatory and Autoimmune Disease

29 Croft (2010) 29

Blocking OX40 does not prevent primary protective immune responses to acute infections Immunosuppressive effect observed only in chronic (memory) responses infections

Pathogen Mice or reagents Type of infection Response phenotype Reference

Leishmania major

OX40-- acute Normal clearance (C57BL6) Decreased pathology in BALBC J Immunol 1999 Dec 15163(12)6520-9

OX40L acute

Normal clearance (C57BL6) Decreased non protective TH2 response in BALBC J Exp Med 2000 Jan 17191(2)375-80

Nippostrongylus brasiliensis

OX40-- acute

Normal clearance Normal TH2 cytokines J Immunol 1999 Dec 15163(12)6520-9

Heligmosomoides polygyrus

OX40L-- chronic Increased infectivity Memory response altered J Immunol 2003 Jan 1170(1)384-

93

mCMV acute phase

OX40-- acute

Normal response

Weaker CD4 T cell response Normal CD8 and Ab response

J Immunol 2007 Aug 15179(4)2195-202

mCMV chronic phase

OX40--

chronic

Defective response Decreased long term CD8 and antibody response J Immunol 2007 Aug 15179(4)2195-202

VSV OX40-- OX40L--

acute

Normal clearance

Normal Ab response Reduced memory response

Immunity 1999 Dec11(6)699-708 Immunity 1999 Dec11(6)689-98

Theilers murine encephalomyelitis virus

OX40-- acute

Normal clearance Normal CD8 response J Immunol 1999 Dec 15163(12)6520-9

Influenza OX40-- OX40-Ig

acute

Normal clearance

Reduced pulmonary CD4 and CD8 normal Ab response Reduced immunopathology

Immunity 1999 Dec11(6)699-708 J Immunol 2005 Aug 1175(3)1665-76 J Exp Med 2003 Oct 20198(8)1237-42

Acute LCMV OX40-- acute

Normal response Normal primary and memory CD8 response Decreased CD4 response Normal Ab response

Immunity 1999 Dec11(6)699-708

Persistent LCMV OX40-- chronic

Defective response

Decrease initial pathology but impaired anti viral T cell accumulation

PLoS Pathog 2012 Sep8(9

Mycobacterium avium

OX40L acute

Normal clearance

J Leukoc Biol 2004 Nov76(5)1039-46

Listeria monocytogenes OX40-- acute

Normal primary response and clearance

Normal primary CD8 Decreased long term and memory CD8 J Immunol 2008 Nov 1181(9)5990-6001

30

ProtozoaNematode

Virus

Bacteria

Translational Validation of OX40-OX40L Axis in Human Disease States

31

bull Tissue Expression ndash Psoriasis (Matsumura Arch Dermatol res 2003)

ndash Atopic dermatitis (Ilves J Eur Acad Dermatol Venereol 2013)

ndash RA (Giacomelli Clin Exp Rheumatol 2001 Brugnoni Br J Rheumatol 1998)

ndash IBD (Souza Gut 1999 Stuumlber Eur J Clin Invest 2000)

ndash Lupus (Dolff Arthritis Res Ther 2010 Aten J J Am Soc Nephrol 2000 Patschan S Clin Exp Immunol 2006)

Atopic dermatitis

Psoriasis

Healthy control

Healthy control

OX40 immunohistology

Lupus nephritis

Ilves et al

Dolff et al

Souza et al

Patschan et al

SLE

IBD

CD3+ OX40+ CD4+ OX40+

SF Synovial fluid PB peripheral blood

Giacomelli et al

OX40 flow cytometry

Colon

Peripheral blood

GBR 830 Blocks OX40OX40L Interaction and has cytotoxic potential

32

ELISA anti BrdU Readout cell proliferation

ADCC on HPB-ALL (OX40+ T lymphoma line)

OX

40

L

OX

40

T

C

R

OX

40

LOKT3

T-cell

OX

40

-Fc

OX

40

-Fc

OX

40

-Fc

OX

40

L

OX

40

L

OX

40

L

-4 -3 -2 -1 0 1 200

05

10

Non blocker anti OX40

GBR 830

No Ab

Log antibody concentration (gmL)

OD

(450n

m)

10 10 1 01 001

0

50

100

Isotype control

GBR 830

Antibody concentration (gmL)

Inh

ibit

ion

of

pro

life

rati

on

(

)

-8 -6 -4 -2 0 2 4-10

-5

0

5

10

15

20IgG1 control

GBR 830

GBR 830-IgG4hs


Sp

ecif

ic A

DC

C (

)

Readout Killing

NK cell

T-cell

OX40 Antagonist Inhibits Mixed Lymphocyte Reaction

33

Legend One way mixed lymphocyte reaction (MLR) measured by 3H thymidine incorporation Bars show the mean 3H -thymidine incorporation (counts) of at least triplicates plusmn standard error of the mean Isotype control (trastuzumab) and positive control (efalizumab) are shown Effector stands for only effector cells Effector + target represents a measurement where antibodies have been omitted

bull In vitro validation of inhibition of T-cell proliferation by OX40 antagonist mAb bull Potency on parsuperior to Efalizumab (LFA1 blocker)

effe

ctor

effe

ctor+

targ

et

Isoty

pe co

ntrol (

50ugm

L)

Efaliz

umab

(20u

gml)

Efaliz

umab

(2ugm

l)

Efaliz

umab

(00

2ugm

l)

(50u

gml)

(5ugm

l)

(05

ml)

(00

5ugm

l)

(00

1ugm

l)

(00

01ugm

l)

0

2000

4000

6000

3H

in

co

po

rati

on

(re

lati

ve p

roli

fera

tio

n)

OX40 antagonist

Xenogeneic human graft versus host (mouse) reaction

34

Legend Animals (SCID mice) were sub-lethally irradiated before being reconstituted with 30 million human PBMCs intraperitoneally The mice were also depleted for mouse NK cells by twice weekly injections with the TMbeta1 antibody The treatment with OX40 antagonistic antibody (1 or 10mgkg) Etanercept (a fusion protein of the human soluble TNF receptor 2 fused to the Fc component of human IgG1 Amgen-Pfizer ) or vehicle was given iv weekly for six consecutive doses and started two days before the PBMC injection The animals were checked and scored three times weekly for GVHD symptoms including weight loss diarrhea fur aspect and general behavior Animals were ethically sacrificed if symptoms were considered too severe

Treatment

0 20 40 600

50

100 Vehicle

Enbrel (8mgkg)

OX40 antagonist 1mgkg


days

Perc

en

t su

rviv

al

bull In vivo validation of inhibition of T-cell proliferation and effector function by OX40 antagonist mAb bull Potency superior to Etanercept

GBR 830 displays a potent therapeutic anti-psoriasis effect

35

bull Relevance of the psoriasis plaque transplant model

bull Method Overview ndash Lesional psoriatic patient skin (epiderma+derma) patches are grafted on a SCID mouse

After graft implementation the mice are treated Main readout epidermal thickness and T cell infiltration

bull Advantages ndash Readouts are clinically relevant

ndash Genuine pathologic human tissue

ndash Healing process in grafted tissue due to treatment is very similar to healing of a normal tissue in a patient

ndash Pathology is dependent on leukocytes (mostly activated memory T cells) in the transplant

bull This model is highly predictive of clinical efficacy ndash Therapeutics that have successfully been tested in this model CsA TNF-α blockers

(infliximab etanercept) ustekinumab (anti IL-12IL-23) Anti IL-17 Anti CD11a (raptiva) Anti IL-21)

Effect on psoriasis healing

36

bull Treatment with GBR 830 improved resolution of psoriasis phenotype

bull Same effect observed on all the 5 donors included bull Indicates that targeting OX40 can impact an ongoing

chronic (memory) pathological response

Iso

typ

e

con

tro

l G

BR

83

0

Tem

ova

te

Donor 1-5

Isoty

pe co

ntrol

GBR83

0

Temova

te

0

50

100

150

200

250

Ep

iderm

al

thic

kn

ess (

m)

Donor 1 Donor 4

Iso

typ

e

con

tro

l G

BR

83

0

Tem

ova

te

Glenmarkrsquos BEATreg Technology

Bispecific Antibody Platform

37


Bispecific Antibody

Engineering Platform

Cell-Line Development and

Master-Cell Banking

Manufacturing of Bispecific at Scale

bull Plug and play from existing binders bull Effector functions preserved bull Low mispairing of binders

bull Stable high expression

bull Utilization of standard methods and equipment bull High yield

38

Bispecific Engagement by Antibody based on T-cell receptor

BEATreg technology based on bio-mimicry

39

Engineering of CH3 interface heavy chain heterodimerization technology mimics the natural association of the T-cell surface receptors α and β


Bispecific Antibody



Master-Cell Banking

Manufacturing of Bispecific molecules

bull Nature-like heterodimeric molecule bull Full antibody Fc functions incl half life

bull Industrial relevant expression in CHO cells

bull gt 3gL bull gt 90 heterodimer bull Stable product quality

bull Industrial relevant scalable purification process

bull gt 97 of heterodimer after Protein A

40

T cell-mediated redirected killing - a novel BEATreg mechanism of action

Bridging T cells to tumor cells via anti CD3tumor antigen bispecific molecule allows activation of T cells independently of tumor peptide recognition Leads to redirected lysis (RDL) and death of tumor cell

CD3+ T cell

HER2+ Tumour Cell

41

BEATreg amp CD3 Redirected Killing

bull CD3 x Her2 efficiently kills receptor expressing

cell line

bull picomolar killing activity of BEAT

Legend Effector cells human T-cells Target cells expressing Her2 receptor EffectorTarget = 51 24h incubation readout FACS 7-AADCFSE

42

0

20

40

60

80

100

No Ab

Ctrl BEAT

CD3 x Her2

Concentration (pM)

o

f s

pec

ific

kil

lin

g

CD3 x Her-2 bispecific ndash Her2+ SCID mouse xenograft in vivo model MOA redirected killing JIMT-1 human breast adenocarcinoma ndash resistant to herceptin

Average of tumor growth volume for all mice in all groups


43

44

PUBLISHED APPLICATIONS WO2013183032 HUMANIZED ANTI-TRKA ANTIBODIES WITH AMINO ACID SUBSTITUTIONS WO2013084157 EXPRESSION CASSETTE WO2013008171 ANTIBODIES THAT BIND TO OX40 AND THEIR USES WO2012131555 HETERO-DIMERIC IMMUNOGLOBULINS WO2010095031 HUMANIZED ANTIBODIES THAT BIND TO CD19 AND THEIR USES WO2010052556 TREATMENT WITH ANTI-ALPHA2 INTEGRIN ANTIBODIES WO2009093138 HUMANIZED ANTIBODIES SPECIFIC FOR VON WILLEBRAND FACTOR WO2007056858 ANTI-ALPHA2 INTEGRIN ANTIBODIES AND THEIR USES FILED APPLICATIONS TO BE PUBLISHED PCTEP2013069989 PURIFICATION OF HETERO-DIMERIC IMMUNOGLOBULINS (Pub date scheduled Mar 2014) PCT XXXX ANTIBODIES THAT BIND TO TL1A AND THEIR USES (Pub date scheduled Jun 2014) USXXXX ldquoGBR 200 FORMULATIONrdquo PCTEPXXXX ALTERNATIVE SPLICING

Intellectual Property

45

Thank You

bull Intro ndash Glenmark GBR 910 anti ndashTL1A antibody GBR830 anti-OX40 antibody BEAT bispecific antibody

2





3






2000

Turnover (FY 2012) $919 MN (+24)





2013

API Mfg





4

Global Footprint

5

RampD for Biologics

Switzerland

Glenmark

Generics Ltd US

Glenmark

Generics SA

Argentina

Medicamenta

Czech Republic

Glenmark

Farmacetica Ltda

Brazil

Glenmark Pharma

Europe Limited

London UK

Bowter Bartlett

South Arica

Glenmark

India




6 Discovery

Candidates in

Clinical Trials



6





CFTR Inhibitor




mPGES-1 inhibitors


mPGES-1 inhibitors








NCE

NBE

Crofelemer

GRC 17536


7








8

RampD Biologics


Aspirin

Cyclosporine

9


10

TL1A (TNFSF15)









receptor)



N C

11


12


X

X

X

13



TL1A


Asthma

Multiple sclerosis

(EAE)

Psoriasis





Friel







Selected

References

COPD


atherosclerosis

15





Bowel Dis 2009)


16



0 5 12

-1 0 +1 +2 +3 +4

16



mucus



Ab 50ug ip


17


F480

F480

TL

1A

T

L1

A Naive mouse

Mouse with UC


18


Siglec F PE

CD

11c

AP

C

Siglec F-PE


Eosinophils





19


IL-12 + IL18 - + + + + + +


5G6 (μgml) - - - 10 1 01 -





IC Monocyte

Mb TL1A

T cell

DR3

IFNg

IFNg

IFNg

IFNg

IFNg

IFNg

IFNg



soluble TL1A

T cell

DR3

IFNg

IFNg

IFNg

IFNg

IFNg

IFNg

IFNg

20


Contr

ol iso

Dex

amet

hasone

GBR91

0 (5

0mgk

g)

Nai

ve

00

2000000

4000000

6000000

8000000

nu

mb

er

of

eo

sin

op

hil

s

Her

ceptin

(20m

gkg)

Cyc

losp

orin

5G6

(20m

gkg)

No

DSS

5

6

7

8

colo

n l

eng

th (

cm

)


DSS colitis

OVA-induced asthma

21

Day -1


- Adhesion

- Strictures

- Ulcers

- Wall thickness

- HampE

- PAS

N=8


Body weight

Day 0



Group3 GBR910

Group4 Prednisolone

starvation

+2 hours Day 7

treatment

Colon length

Histology


22

00

05

10

15

20

25

30

35


AV

ER

AG

E C

OLO

NIC

SC

OR

E

COLONIC PARAMETER




23




In vitro activity







24


25






26


27


OX40 (active homo-

trimer)


Activated T-Cell





C D28 signals

memory memory

Naive

Effector


Memory generation



28


OX40 (active homo-

trimer)


Activated T-Cell






Smaller memory pool

Contraction sooner


Weaker reactivation


memory memory Naive

effector


29 Croft (2010) 29



Leishmania major


OX40L acute



OX40-- acute




93

mCMV acute phase

OX40-- acute

Normal response


J Immunol 2007 Aug 15179(4)2195-202

mCMV chronic phase

OX40--

chronic


VSV OX40-- OX40L--

acute

Normal clearance




OX40-- acute



acute

Normal clearance





Immunity 1999 Dec11(6)699-708


Defective response



Mycobacterium avium

OX40L acute

Normal clearance





30

ProtozoaNematode

Virus

Bacteria


31






Atopic dermatitis

Psoriasis

Healthy control

Healthy control


Lupus nephritis

Ilves et al

Dolff et al

Souza et al

Patschan et al

SLE

IBD

CD3+ OX40+ CD4+ OX40+


Giacomelli et al

OX40 flow cytometry

Colon

Peripheral blood


32



OX

40

L

OX

40

T

C

R

OX

40

LOKT3

T-cell

OX

40

-Fc

OX

40

-Fc

OX

40

-Fc

OX

40

L

OX

40

L

OX

40

L

-4 -3 -2 -1 0 1 200

05

10


GBR 830

No Ab


OD

(450n

m)

10 10 1 01 001

0

50

100

Isotype control

GBR 830


Inh

ibit

ion

of

pro

life

rati

on

(

)

-8 -6 -4 -2 0 2 4-10

-5

0

5

10

15

20IgG1 control

GBR 830

GBR 830-IgG4hs


Sp

ecif

ic A

DC

C (

)

Readout Killing

NK cell

T-cell


33



effe

ctor

effe

ctor+

targ

et

Isoty

pe co

ntrol (

50ugm

L)

Efaliz

umab

(20u

gml)

Efaliz

umab

(2ugm

l)

Efaliz

umab

(00

2ugm

l)

(50u

gml)

(5ugm

l)

(05

ml)

(00

5ugm

l)

(00

1ugm

l)

(00

01ugm

l)

0

2000

4000

6000

3H

in

co

po

rati

on

(re

lati

ve p

roli

fera

tio

n)

OX40 antagonist


34


Treatment

0 20 40 600

50

100 Vehicle

Enbrel (8mgkg)



days

Perc

en

t su

rviv

al



35











36




Iso

typ

e

con

tro

l G

BR

83

0

Tem

ova

te

Donor 1-5

Isoty

pe co

ntrol

GBR83

0

Temova

te

0

50

100

150

200

250

Ep

iderm

al

thic

kn

ess (

m)

Donor 1 Donor 4

Iso

typ

e

con

tro

l G

BR

83

0

Tem

ova

te



37


Bispecific Antibody



Master-Cell Banking





38



39



Bispecific Antibody



Master-Cell Banking







40



CD3+ T cell

HER2+ Tumour Cell

41



cell line



42

0

20

40

60

80

100

No Ab

Ctrl BEAT

CD3 x Her2

Concentration (pM)

o

f s

pec

ific

kil

lin

g




43

44



45

Thank You





3






2000

Turnover (FY 2012) $919 MN (+24)





2013

API Mfg





4

Global Footprint

5

RampD for Biologics

Switzerland

Glenmark

Generics Ltd US

Glenmark

Generics SA

Argentina

Medicamenta

Czech Republic

Glenmark

Farmacetica Ltda

Brazil

Glenmark Pharma

Europe Limited

London UK

Bowter Bartlett

South Arica

Glenmark

India




6 Discovery

Candidates in

Clinical Trials



6





CFTR Inhibitor




mPGES-1 inhibitors


mPGES-1 inhibitors








NCE

NBE

Crofelemer

GRC 17536


7








8

RampD Biologics


Aspirin

Cyclosporine

9


10

TL1A (TNFSF15)









receptor)



N C

11


12


X

X

X

13



TL1A


Asthma

Multiple sclerosis

(EAE)

Psoriasis





Friel







Selected

References

COPD


atherosclerosis

15





Bowel Dis 2009)


16



0 5 12

-1 0 +1 +2 +3 +4

16



mucus



Ab 50ug ip


17


F480

F480

TL

1A

T

L1

A Naive mouse

Mouse with UC


18


Siglec F PE

CD

11c

AP

C

Siglec F-PE


Eosinophils





19


IL-12 + IL18 - + + + + + +


5G6 (μgml) - - - 10 1 01 -





IC Monocyte

Mb TL1A

T cell

DR3

IFNg

IFNg

IFNg

IFNg

IFNg

IFNg

IFNg



soluble TL1A

T cell

DR3

IFNg

IFNg

IFNg

IFNg

IFNg

IFNg

IFNg

20


Contr

ol iso

Dex

amet

hasone

GBR91

0 (5

0mgk

g)

Nai

ve

00

2000000

4000000

6000000

8000000

nu

mb

er

of

eo

sin

op

hil

s

Her

ceptin

(20m

gkg)

Cyc

losp

orin

5G6

(20m

gkg)

No

DSS

5

6

7

8

colo

n l

eng

th (

cm

)


DSS colitis

OVA-induced asthma

21

Day -1


- Adhesion

- Strictures

- Ulcers

- Wall thickness

- HampE

- PAS

N=8


Body weight

Day 0



Group3 GBR910

Group4 Prednisolone

starvation

+2 hours Day 7

treatment

Colon length

Histology


22

00

05

10

15

20

25

30

35


AV

ER

AG

E C

OLO

NIC

SC

OR

E

COLONIC PARAMETER




23




In vitro activity







24


25






26


27


OX40 (active homo-

trimer)


Activated T-Cell





C D28 signals

memory memory

Naive

Effector


Memory generation



28


OX40 (active homo-

trimer)


Activated T-Cell






Smaller memory pool

Contraction sooner


Weaker reactivation


memory memory Naive

effector


29 Croft (2010) 29



Leishmania major


OX40L acute



OX40-- acute




93

mCMV acute phase

OX40-- acute

Normal response


J Immunol 2007 Aug 15179(4)2195-202

mCMV chronic phase

OX40--

chronic


VSV OX40-- OX40L--

acute

Normal clearance




OX40-- acute



acute

Normal clearance





Immunity 1999 Dec11(6)699-708


Defective response



Mycobacterium avium

OX40L acute

Normal clearance





30

ProtozoaNematode

Virus

Bacteria


31






Atopic dermatitis

Psoriasis

Healthy control

Healthy control


Lupus nephritis

Ilves et al

Dolff et al

Souza et al

Patschan et al

SLE

IBD

CD3+ OX40+ CD4+ OX40+


Giacomelli et al

OX40 flow cytometry

Colon

Peripheral blood


32



OX

40

L

OX

40

T

C

R

OX

40

LOKT3

T-cell

OX

40

-Fc

OX

40

-Fc

OX

40

-Fc

OX

40

L

OX

40

L

OX

40

L

-4 -3 -2 -1 0 1 200

05

10


GBR 830

No Ab


OD

(450n

m)

10 10 1 01 001

0

50

100

Isotype control

GBR 830


Inh

ibit

ion

of

pro

life

rati

on

(

)

-8 -6 -4 -2 0 2 4-10

-5

0

5

10

15

20IgG1 control

GBR 830

GBR 830-IgG4hs


Sp

ecif

ic A

DC

C (

)

Readout Killing

NK cell

T-cell


33



effe

ctor

effe

ctor+

targ

et

Isoty

pe co

ntrol (

50ugm

L)

Efaliz

umab

(20u

gml)

Efaliz

umab

(2ugm

l)

Efaliz

umab

(00

2ugm

l)

(50u

gml)

(5ugm

l)

(05

ml)

(00

5ugm

l)

(00

1ugm

l)

(00

01ugm

l)

0

2000

4000

6000

3H

in

co

po

rati

on

(re

lati

ve p

roli

fera

tio

n)

OX40 antagonist


34


Treatment

0 20 40 600

50

100 Vehicle

Enbrel (8mgkg)



days

Perc

en

t su

rviv

al



35











36




Iso

typ

e

con

tro

l G

BR

83

0

Tem

ova

te

Donor 1-5

Isoty

pe co

ntrol

GBR83

0

Temova

te

0

50

100

150

200

250

Ep

iderm

al

thic

kn

ess (

m)

Donor 1 Donor 4

Iso

typ

e

con

tro

l G

BR

83

0

Tem

ova

te



37


Bispecific Antibody



Master-Cell Banking





38



39



Bispecific Antibody



Master-Cell Banking







40



CD3+ T cell

HER2+ Tumour Cell

41



cell line



42

0

20

40

60

80

100

No Ab

Ctrl BEAT

CD3 x Her2

Concentration (pM)

o

f s

pec

ific

kil

lin

g




43

44



45

Thank You






2000

Turnover (FY 2012) $919 MN (+24)





2013

API Mfg





4

Global Footprint

5

RampD for Biologics

Switzerland

Glenmark

Generics Ltd US

Glenmark

Generics SA

Argentina

Medicamenta

Czech Republic

Glenmark

Farmacetica Ltda

Brazil

Glenmark Pharma

Europe Limited

London UK

Bowter Bartlett

South Arica

Glenmark

India




6 Discovery

Candidates in

Clinical Trials



6





CFTR Inhibitor




mPGES-1 inhibitors


mPGES-1 inhibitors








NCE

NBE

Crofelemer

GRC 17536


7








8

RampD Biologics


Aspirin

Cyclosporine

9


10

TL1A (TNFSF15)









receptor)



N C

11


12


X

X

X

13



TL1A


Asthma

Multiple sclerosis

(EAE)

Psoriasis





Friel







Selected

References

COPD


atherosclerosis

15





Bowel Dis 2009)


16



0 5 12

-1 0 +1 +2 +3 +4

16



mucus



Ab 50ug ip


17


F480

F480

TL

1A

T

L1

A Naive mouse

Mouse with UC


18


Siglec F PE

CD

11c

AP

C

Siglec F-PE


Eosinophils





19


IL-12 + IL18 - + + + + + +


5G6 (μgml) - - - 10 1 01 -





IC Monocyte

Mb TL1A

T cell

DR3

IFNg

IFNg

IFNg

IFNg

IFNg

IFNg

IFNg



soluble TL1A

T cell

DR3

IFNg

IFNg

IFNg

IFNg

IFNg

IFNg

IFNg

20


Contr

ol iso

Dex

amet

hasone

GBR91

0 (5

0mgk

g)

Nai

ve

00

2000000

4000000

6000000

8000000

nu

mb

er

of

eo

sin

op

hil

s

Her

ceptin

(20m

gkg)

Cyc

losp

orin

5G6

(20m

gkg)

No

DSS

5

6

7

8

colo

n l

eng

th (

cm

)


DSS colitis

OVA-induced asthma

21

Day -1


- Adhesion

- Strictures

- Ulcers

- Wall thickness

- HampE

- PAS

N=8


Body weight

Day 0



Group3 GBR910

Group4 Prednisolone

starvation

+2 hours Day 7

treatment

Colon length

Histology


22

00

05

10

15

20

25

30

35


AV

ER

AG

E C

OLO

NIC

SC

OR

E

COLONIC PARAMETER




23




In vitro activity







24


25






26


27


OX40 (active homo-

trimer)


Activated T-Cell





C D28 signals

memory memory

Naive

Effector


Memory generation



28


OX40 (active homo-

trimer)


Activated T-Cell






Smaller memory pool

Contraction sooner


Weaker reactivation


memory memory Naive

effector


29 Croft (2010) 29



Leishmania major


OX40L acute



OX40-- acute




93

mCMV acute phase

OX40-- acute

Normal response


J Immunol 2007 Aug 15179(4)2195-202

mCMV chronic phase

OX40--

chronic


VSV OX40-- OX40L--

acute

Normal clearance




OX40-- acute



acute

Normal clearance





Immunity 1999 Dec11(6)699-708


Defective response



Mycobacterium avium

OX40L acute

Normal clearance





30

ProtozoaNematode

Virus

Bacteria


31






Atopic dermatitis

Psoriasis

Healthy control

Healthy control


Lupus nephritis

Ilves et al

Dolff et al

Souza et al

Patschan et al

SLE

IBD

CD3+ OX40+ CD4+ OX40+


Giacomelli et al

OX40 flow cytometry

Colon

Peripheral blood


32



OX

40

L

OX

40

T

C

R

OX

40

LOKT3

T-cell

OX

40

-Fc

OX

40

-Fc

OX

40

-Fc

OX

40

L

OX

40

L

OX

40

L

-4 -3 -2 -1 0 1 200

05

10


GBR 830

No Ab


OD

(450n

m)

10 10 1 01 001

0

50

100

Isotype control

GBR 830


Inh

ibit

ion

of

pro

life

rati

on

(

)

-8 -6 -4 -2 0 2 4-10

-5

0

5

10

15

20IgG1 control

GBR 830

GBR 830-IgG4hs


Sp

ecif

ic A

DC

C (

)

Readout Killing

NK cell

T-cell


33



effe

ctor

effe

ctor+

targ

et

Isoty

pe co

ntrol (

50ugm

L)

Efaliz

umab

(20u

gml)

Efaliz

umab

(2ugm

l)

Efaliz

umab

(00

2ugm

l)

(50u

gml)

(5ugm

l)

(05

ml)

(00

5ugm

l)

(00

1ugm

l)

(00

01ugm

l)

0

2000

4000

6000

3H

in

co

po

rati

on

(re

lati

ve p

roli

fera

tio

n)

OX40 antagonist


34


Treatment

0 20 40 600

50

100 Vehicle

Enbrel (8mgkg)



days

Perc

en

t su

rviv

al



35











36




Iso

typ

e

con

tro

l G

BR

83

0

Tem

ova

te

Donor 1-5

Isoty

pe co

ntrol

GBR83

0

Temova

te

0

50

100

150

200

250

Ep

iderm

al

thic

kn

ess (

m)

Donor 1 Donor 4

Iso

typ

e

con

tro

l G

BR

83

0

Tem

ova

te



37


Bispecific Antibody



Master-Cell Banking





38



39



Bispecific Antibody



Master-Cell Banking







40



CD3+ T cell

HER2+ Tumour Cell

41



cell line



42

0

20

40

60

80

100

No Ab

Ctrl BEAT

CD3 x Her2

Concentration (pM)

o

f s

pec

ific

kil

lin

g




43

44



45

Thank You

Global Footprint

5

RampD for Biologics

Switzerland

Glenmark

Generics Ltd US

Glenmark

Generics SA

Argentina

Medicamenta

Czech Republic

Glenmark

Farmacetica Ltda

Brazil

Glenmark Pharma

Europe Limited

London UK

Bowter Bartlett

South Arica

Glenmark

India




6 Discovery

Candidates in

Clinical Trials



6





CFTR Inhibitor




mPGES-1 inhibitors


mPGES-1 inhibitors








NCE

NBE

Crofelemer

GRC 17536


7








8

RampD Biologics


Aspirin

Cyclosporine

9


10

TL1A (TNFSF15)









receptor)



N C

11


12


X

X

X

13



TL1A


Asthma

Multiple sclerosis

(EAE)

Psoriasis





Friel







Selected

References

COPD


atherosclerosis

15





Bowel Dis 2009)


16



0 5 12

-1 0 +1 +2 +3 +4

16



mucus



Ab 50ug ip


17


F480

F480

TL

1A

T

L1

A Naive mouse

Mouse with UC


18


Siglec F PE

CD

11c

AP

C

Siglec F-PE


Eosinophils





19


IL-12 + IL18 - + + + + + +


5G6 (μgml) - - - 10 1 01 -





IC Monocyte

Mb TL1A

T cell

DR3

IFNg

IFNg

IFNg

IFNg

IFNg

IFNg

IFNg



soluble TL1A

T cell

DR3

IFNg

IFNg

IFNg

IFNg

IFNg

IFNg

IFNg

20


Contr

ol iso

Dex

amet

hasone

GBR91

0 (5

0mgk

g)

Nai

ve

00

2000000

4000000

6000000

8000000

nu

mb

er

of

eo

sin

op

hil

s

Her

ceptin

(20m

gkg)

Cyc

losp

orin

5G6

(20m

gkg)

No

DSS

5

6

7

8

colo

n l

eng

th (

cm

)


DSS colitis

OVA-induced asthma

21

Day -1


- Adhesion

- Strictures

- Ulcers

- Wall thickness

- HampE

- PAS

N=8


Body weight

Day 0



Group3 GBR910

Group4 Prednisolone

starvation

+2 hours Day 7

treatment

Colon length

Histology


22

00

05

10

15

20

25

30

35


AV

ER

AG

E C

OLO

NIC

SC

OR

E

COLONIC PARAMETER




23




In vitro activity







24


25






26


27


OX40 (active homo-

trimer)


Activated T-Cell





C D28 signals

memory memory

Naive

Effector


Memory generation



28


OX40 (active homo-

trimer)


Activated T-Cell






Smaller memory pool

Contraction sooner


Weaker reactivation


memory memory Naive

effector


29 Croft (2010) 29



Leishmania major


OX40L acute



OX40-- acute




93

mCMV acute phase

OX40-- acute

Normal response


J Immunol 2007 Aug 15179(4)2195-202

mCMV chronic phase

OX40--

chronic


VSV OX40-- OX40L--

acute

Normal clearance




OX40-- acute



acute

Normal clearance





Immunity 1999 Dec11(6)699-708


Defective response



Mycobacterium avium

OX40L acute

Normal clearance





30

ProtozoaNematode

Virus

Bacteria


31






Atopic dermatitis

Psoriasis

Healthy control

Healthy control


Lupus nephritis

Ilves et al

Dolff et al

Souza et al

Patschan et al

SLE

IBD

CD3+ OX40+ CD4+ OX40+


Giacomelli et al

OX40 flow cytometry

Colon

Peripheral blood


32



OX

40

L

OX

40

T

C

R

OX

40

LOKT3

T-cell

OX

40

-Fc

OX

40

-Fc

OX

40

-Fc

OX

40

L

OX

40

L

OX

40

L

-4 -3 -2 -1 0 1 200

05

10


GBR 830

No Ab


OD

(450n

m)

10 10 1 01 001

0

50

100

Isotype control

GBR 830


Inh

ibit

ion

of

pro

life

rati

on

(

)

-8 -6 -4 -2 0 2 4-10

-5

0

5

10

15

20IgG1 control

GBR 830

GBR 830-IgG4hs


Sp

ecif

ic A

DC

C (

)

Readout Killing

NK cell

T-cell


33



effe

ctor

effe

ctor+

targ

et

Isoty

pe co

ntrol (

50ugm

L)

Efaliz

umab

(20u

gml)

Efaliz

umab

(2ugm

l)

Efaliz

umab

(00

2ugm

l)

(50u

gml)

(5ugm

l)

(05

ml)

(00

5ugm

l)

(00

1ugm

l)

(00

01ugm

l)

0

2000

4000

6000

3H

in

co

po

rati

on

(re

lati

ve p

roli

fera

tio

n)

OX40 antagonist


34


Treatment

0 20 40 600

50

100 Vehicle

Enbrel (8mgkg)



days

Perc

en

t su

rviv

al



35











36




Iso

typ

e

con

tro

l G

BR

83

0

Tem

ova

te

Donor 1-5

Isoty

pe co

ntrol

GBR83

0

Temova

te

0

50

100

150

200

250

Ep

iderm

al

thic

kn

ess (

m)

Donor 1 Donor 4

Iso

typ

e

con

tro

l G

BR

83

0

Tem

ova

te



37


Bispecific Antibody



Master-Cell Banking





38



39



Bispecific Antibody



Master-Cell Banking







40



CD3+ T cell

HER2+ Tumour Cell

41



cell line



42

0

20

40

60

80

100

No Ab

Ctrl BEAT

CD3 x Her2

Concentration (pM)

o

f s

pec

ific

kil

lin

g




43

44



45

Thank You



6 Discovery

Candidates in

Clinical Trials



6





CFTR Inhibitor




mPGES-1 inhibitors


mPGES-1 inhibitors








NCE

NBE

Crofelemer

GRC 17536


7








8

RampD Biologics


Aspirin

Cyclosporine

9


10

TL1A (TNFSF15)









receptor)



N C

11


12


X

X

X

13



TL1A


Asthma

Multiple sclerosis

(EAE)

Psoriasis





Friel







Selected

References

COPD


atherosclerosis

15





Bowel Dis 2009)


16



0 5 12

-1 0 +1 +2 +3 +4

16



mucus



Ab 50ug ip


17


F480

F480

TL

1A

T

L1

A Naive mouse

Mouse with UC


18


Siglec F PE

CD

11c

AP

C

Siglec F-PE


Eosinophils





19


IL-12 + IL18 - + + + + + +


5G6 (μgml) - - - 10 1 01 -





IC Monocyte

Mb TL1A

T cell

DR3

IFNg

IFNg

IFNg

IFNg

IFNg

IFNg

IFNg



soluble TL1A

T cell

DR3

IFNg

IFNg

IFNg

IFNg

IFNg

IFNg

IFNg

20


Contr

ol iso

Dex

amet

hasone

GBR91

0 (5

0mgk

g)

Nai

ve

00

2000000

4000000

6000000

8000000

nu

mb

er

of

eo

sin

op

hil

s

Her

ceptin

(20m

gkg)

Cyc

losp

orin

5G6

(20m

gkg)

No

DSS

5

6

7

8

colo

n l

eng

th (

cm

)


DSS colitis

OVA-induced asthma

21

Day -1


- Adhesion

- Strictures

- Ulcers

- Wall thickness

- HampE

- PAS

N=8


Body weight

Day 0



Group3 GBR910

Group4 Prednisolone

starvation

+2 hours Day 7

treatment

Colon length

Histology


22

00

05

10

15

20

25

30

35


AV

ER

AG

E C

OLO

NIC

SC

OR

E

COLONIC PARAMETER




23




In vitro activity







24


25






26


27


OX40 (active homo-

trimer)


Activated T-Cell





C D28 signals

memory memory

Naive

Effector


Memory generation



28


OX40 (active homo-

trimer)


Activated T-Cell






Smaller memory pool

Contraction sooner


Weaker reactivation


memory memory Naive

effector


29 Croft (2010) 29



Leishmania major


OX40L acute



OX40-- acute




93

mCMV acute phase

OX40-- acute

Normal response


J Immunol 2007 Aug 15179(4)2195-202

mCMV chronic phase

OX40--

chronic


VSV OX40-- OX40L--

acute

Normal clearance




OX40-- acute



acute

Normal clearance





Immunity 1999 Dec11(6)699-708


Defective response



Mycobacterium avium

OX40L acute

Normal clearance





30

ProtozoaNematode

Virus

Bacteria


31






Atopic dermatitis

Psoriasis

Healthy control

Healthy control


Lupus nephritis

Ilves et al

Dolff et al

Souza et al

Patschan et al

SLE

IBD

CD3+ OX40+ CD4+ OX40+


Giacomelli et al

OX40 flow cytometry

Colon

Peripheral blood


32



OX

40

L

OX

40

T

C

R

OX

40

LOKT3

T-cell

OX

40

-Fc

OX

40

-Fc

OX

40

-Fc

OX

40

L

OX

40

L

OX

40

L

-4 -3 -2 -1 0 1 200

05

10


GBR 830

No Ab


OD

(450n

m)

10 10 1 01 001

0

50

100

Isotype control

GBR 830


Inh

ibit

ion

of

pro

life

rati

on

(

)

-8 -6 -4 -2 0 2 4-10

-5

0

5

10

15

20IgG1 control

GBR 830

GBR 830-IgG4hs


Sp

ecif

ic A

DC

C (

)

Readout Killing

NK cell

T-cell


33



effe

ctor

effe

ctor+

targ

et

Isoty

pe co

ntrol (

50ugm

L)

Efaliz

umab

(20u

gml)

Efaliz

umab

(2ugm

l)

Efaliz

umab

(00

2ugm

l)

(50u

gml)

(5ugm

l)

(05

ml)

(00

5ugm

l)

(00

1ugm

l)

(00

01ugm

l)

0

2000

4000

6000

3H

in

co

po

rati

on

(re

lati

ve p

roli

fera

tio

n)

OX40 antagonist


34


Treatment

0 20 40 600

50

100 Vehicle

Enbrel (8mgkg)



days

Perc

en

t su

rviv

al



35











36




Iso

typ

e

con

tro

l G

BR

83

0

Tem

ova

te

Donor 1-5

Isoty

pe co

ntrol

GBR83

0

Temova

te

0

50

100

150

200

250

Ep

iderm

al

thic

kn

ess (

m)

Donor 1 Donor 4

Iso

typ

e

con

tro

l G

BR

83

0

Tem

ova

te



37


Bispecific Antibody



Master-Cell Banking





38



39



Bispecific Antibody



Master-Cell Banking







40



CD3+ T cell

HER2+ Tumour Cell

41



cell line



42

0

20

40

60

80

100

No Ab

Ctrl BEAT

CD3 x Her2

Concentration (pM)

o

f s

pec

ific

kil

lin

g




43

44



45

Thank You





CFTR Inhibitor




mPGES-1 inhibitors


mPGES-1 inhibitors








NCE

NBE

Crofelemer

GRC 17536


7








8

RampD Biologics


Aspirin

Cyclosporine

9


10

TL1A (TNFSF15)









receptor)



N C

11


12


X

X

X

13



TL1A


Asthma

Multiple sclerosis

(EAE)

Psoriasis





Friel







Selected

References

COPD


atherosclerosis

15





Bowel Dis 2009)


16



0 5 12

-1 0 +1 +2 +3 +4

16



mucus



Ab 50ug ip


17


F480

F480

TL

1A

T

L1

A Naive mouse

Mouse with UC


18


Siglec F PE

CD

11c

AP

C

Siglec F-PE


Eosinophils





19


IL-12 + IL18 - + + + + + +


5G6 (μgml) - - - 10 1 01 -





IC Monocyte

Mb TL1A

T cell

DR3

IFNg

IFNg

IFNg

IFNg

IFNg

IFNg

IFNg



soluble TL1A

T cell

DR3

IFNg

IFNg

IFNg

IFNg

IFNg

IFNg

IFNg

20


Contr

ol iso

Dex

amet

hasone

GBR91

0 (5

0mgk

g)

Nai

ve

00

2000000

4000000

6000000

8000000

nu

mb

er

of

eo

sin

op

hil

s

Her

ceptin

(20m

gkg)

Cyc

losp

orin

5G6

(20m

gkg)

No

DSS

5

6

7

8

colo

n l

eng

th (

cm

)


DSS colitis

OVA-induced asthma

21

Day -1


- Adhesion

- Strictures

- Ulcers

- Wall thickness

- HampE

- PAS

N=8


Body weight

Day 0



Group3 GBR910

Group4 Prednisolone

starvation

+2 hours Day 7

treatment

Colon length

Histology


22

00

05

10

15

20

25

30

35


AV

ER

AG

E C

OLO

NIC

SC

OR

E

COLONIC PARAMETER




23




In vitro activity







24


25






26


27


OX40 (active homo-

trimer)


Activated T-Cell





C D28 signals

memory memory

Naive

Effector


Memory generation



28


OX40 (active homo-

trimer)


Activated T-Cell






Smaller memory pool

Contraction sooner


Weaker reactivation


memory memory Naive

effector


29 Croft (2010) 29



Leishmania major


OX40L acute



OX40-- acute




93

mCMV acute phase

OX40-- acute

Normal response


J Immunol 2007 Aug 15179(4)2195-202

mCMV chronic phase

OX40--

chronic


VSV OX40-- OX40L--

acute

Normal clearance




OX40-- acute



acute

Normal clearance





Immunity 1999 Dec11(6)699-708


Defective response



Mycobacterium avium

OX40L acute

Normal clearance





30

ProtozoaNematode

Virus

Bacteria


31






Atopic dermatitis

Psoriasis

Healthy control

Healthy control


Lupus nephritis

Ilves et al

Dolff et al

Souza et al

Patschan et al

SLE

IBD

CD3+ OX40+ CD4+ OX40+


Giacomelli et al

OX40 flow cytometry

Colon

Peripheral blood


32



OX

40

L

OX

40

T

C

R

OX

40

LOKT3

T-cell

OX

40

-Fc

OX

40

-Fc

OX

40

-Fc

OX

40

L

OX

40

L

OX

40

L

-4 -3 -2 -1 0 1 200

05

10


GBR 830

No Ab


OD

(450n

m)

10 10 1 01 001

0

50

100

Isotype control

GBR 830


Inh

ibit

ion

of

pro

life

rati

on

(

)

-8 -6 -4 -2 0 2 4-10

-5

0

5

10

15

20IgG1 control

GBR 830

GBR 830-IgG4hs


Sp

ecif

ic A

DC

C (

)

Readout Killing

NK cell

T-cell


33



effe

ctor

effe

ctor+

targ

et

Isoty

pe co

ntrol (

50ugm

L)

Efaliz

umab

(20u

gml)

Efaliz

umab

(2ugm

l)

Efaliz

umab

(00

2ugm

l)

(50u

gml)

(5ugm

l)

(05

ml)

(00

5ugm

l)

(00

1ugm

l)

(00

01ugm

l)

0

2000

4000

6000

3H

in

co

po

rati

on

(re

lati

ve p

roli

fera

tio

n)

OX40 antagonist


34


Treatment

0 20 40 600

50

100 Vehicle

Enbrel (8mgkg)



days

Perc

en

t su

rviv

al



35











36




Iso

typ

e

con

tro

l G

BR

83

0

Tem

ova

te

Donor 1-5

Isoty

pe co

ntrol

GBR83

0

Temova

te

0

50

100

150

200

250

Ep

iderm

al

thic

kn

ess (

m)

Donor 1 Donor 4

Iso

typ

e

con

tro

l G

BR

83

0

Tem

ova

te



37


Bispecific Antibody



Master-Cell Banking





38



39



Bispecific Antibody



Master-Cell Banking







40



CD3+ T cell

HER2+ Tumour Cell

41



cell line



42

0

20

40

60

80

100

No Ab

Ctrl BEAT

CD3 x Her2

Concentration (pM)

o

f s

pec

ific

kil

lin

g




43

44



45

Thank You








8

RampD Biologics


Aspirin

Cyclosporine

9


10

TL1A (TNFSF15)









receptor)



N C

11


12


X

X

X

13



TL1A


Asthma

Multiple sclerosis

(EAE)

Psoriasis





Friel







Selected

References

COPD


atherosclerosis

15





Bowel Dis 2009)


16



0 5 12

-1 0 +1 +2 +3 +4

16



mucus



Ab 50ug ip


17


F480

F480

TL

1A

T

L1

A Naive mouse

Mouse with UC


18


Siglec F PE

CD

11c

AP

C

Siglec F-PE


Eosinophils





19


IL-12 + IL18 - + + + + + +


5G6 (μgml) - - - 10 1 01 -





IC Monocyte

Mb TL1A

T cell

DR3

IFNg

IFNg

IFNg

IFNg

IFNg

IFNg

IFNg



soluble TL1A

T cell

DR3

IFNg

IFNg

IFNg

IFNg

IFNg

IFNg

IFNg

20


Contr

ol iso

Dex

amet

hasone

GBR91

0 (5

0mgk

g)

Nai

ve

00

2000000

4000000

6000000

8000000

nu

mb

er

of

eo

sin

op

hil

s

Her

ceptin

(20m

gkg)

Cyc

losp

orin

5G6

(20m

gkg)

No

DSS

5

6

7

8

colo

n l

eng

th (

cm

)


DSS colitis

OVA-induced asthma

21

Day -1


- Adhesion

- Strictures

- Ulcers

- Wall thickness

- HampE

- PAS

N=8


Body weight

Day 0



Group3 GBR910

Group4 Prednisolone

starvation

+2 hours Day 7

treatment

Colon length

Histology


22

00

05

10

15

20

25

30

35


AV

ER

AG

E C

OLO

NIC

SC

OR

E

COLONIC PARAMETER




23




In vitro activity







24


25






26


27


OX40 (active homo-

trimer)


Activated T-Cell





C D28 signals

memory memory

Naive

Effector


Memory generation



28


OX40 (active homo-

trimer)


Activated T-Cell






Smaller memory pool

Contraction sooner


Weaker reactivation


memory memory Naive

effector


29 Croft (2010) 29



Leishmania major


OX40L acute



OX40-- acute




93

mCMV acute phase

OX40-- acute

Normal response


J Immunol 2007 Aug 15179(4)2195-202

mCMV chronic phase

OX40--

chronic


VSV OX40-- OX40L--

acute

Normal clearance




OX40-- acute



acute

Normal clearance





Immunity 1999 Dec11(6)699-708


Defective response



Mycobacterium avium

OX40L acute

Normal clearance





30

ProtozoaNematode

Virus

Bacteria


31






Atopic dermatitis

Psoriasis

Healthy control

Healthy control


Lupus nephritis

Ilves et al

Dolff et al

Souza et al

Patschan et al

SLE

IBD

CD3+ OX40+ CD4+ OX40+


Giacomelli et al

OX40 flow cytometry

Colon

Peripheral blood


32



OX

40

L

OX

40

T

C

R

OX

40

LOKT3

T-cell

OX

40

-Fc

OX

40

-Fc

OX

40

-Fc

OX

40

L

OX

40

L

OX

40

L

-4 -3 -2 -1 0 1 200

05

10


GBR 830

No Ab


OD

(450n

m)

10 10 1 01 001

0

50

100

Isotype control

GBR 830


Inh

ibit

ion

of

pro

life

rati

on

(

)

-8 -6 -4 -2 0 2 4-10

-5

0

5

10

15

20IgG1 control

GBR 830

GBR 830-IgG4hs


Sp

ecif

ic A

DC

C (

)

Readout Killing

NK cell

T-cell


33



effe

ctor

effe

ctor+

targ

et

Isoty

pe co

ntrol (

50ugm

L)

Efaliz

umab

(20u

gml)

Efaliz

umab

(2ugm

l)

Efaliz

umab

(00

2ugm

l)

(50u

gml)

(5ugm

l)

(05

ml)

(00

5ugm

l)

(00

1ugm

l)

(00

01ugm

l)

0

2000

4000

6000

3H

in

co

po

rati

on

(re

lati

ve p

roli

fera

tio

n)

OX40 antagonist


34


Treatment

0 20 40 600

50

100 Vehicle

Enbrel (8mgkg)



days

Perc

en

t su

rviv

al



35











36




Iso

typ

e

con

tro

l G

BR

83

0

Tem

ova

te

Donor 1-5

Isoty

pe co

ntrol

GBR83

0

Temova

te

0

50

100

150

200

250

Ep

iderm

al

thic

kn

ess (

m)

Donor 1 Donor 4

Iso

typ

e

con

tro

l G

BR

83

0

Tem

ova

te



37


Bispecific Antibody



Master-Cell Banking





38



39



Bispecific Antibody



Master-Cell Banking







40



CD3+ T cell

HER2+ Tumour Cell

41



cell line



42

0

20

40

60

80

100

No Ab

Ctrl BEAT

CD3 x Her2

Concentration (pM)

o

f s

pec

ific

kil

lin

g




43

44



45

Thank You

RampD Biologics


Aspirin

Cyclosporine

9


10

TL1A (TNFSF15)









receptor)



N C

11


12


X

X

X

13



TL1A


Asthma

Multiple sclerosis

(EAE)

Psoriasis





Friel







Selected

References

COPD


atherosclerosis

15





Bowel Dis 2009)


16



0 5 12

-1 0 +1 +2 +3 +4

16



mucus



Ab 50ug ip


17


F480

F480

TL

1A

T

L1

A Naive mouse

Mouse with UC


18


Siglec F PE

CD

11c

AP

C

Siglec F-PE


Eosinophils





19


IL-12 + IL18 - + + + + + +


5G6 (μgml) - - - 10 1 01 -





IC Monocyte

Mb TL1A

T cell

DR3

IFNg

IFNg

IFNg

IFNg

IFNg

IFNg

IFNg



soluble TL1A

T cell

DR3

IFNg

IFNg

IFNg

IFNg

IFNg

IFNg

IFNg

20


Contr

ol iso

Dex

amet

hasone

GBR91

0 (5

0mgk

g)

Nai

ve

00

2000000

4000000

6000000

8000000

nu

mb

er

of

eo

sin

op

hil

s

Her

ceptin

(20m

gkg)

Cyc

losp

orin

5G6

(20m

gkg)

No

DSS

5

6

7

8

colo

n l

eng

th (

cm

)


DSS colitis

OVA-induced asthma

21

Day -1


- Adhesion

- Strictures

- Ulcers

- Wall thickness

- HampE

- PAS

N=8


Body weight

Day 0



Group3 GBR910

Group4 Prednisolone

starvation

+2 hours Day 7

treatment

Colon length

Histology


22

00

05

10

15

20

25

30

35


AV

ER

AG

E C

OLO

NIC

SC

OR

E

COLONIC PARAMETER




23




In vitro activity







24


25






26


27


OX40 (active homo-

trimer)


Activated T-Cell





C D28 signals

memory memory

Naive

Effector


Memory generation



28


OX40 (active homo-

trimer)


Activated T-Cell






Smaller memory pool

Contraction sooner


Weaker reactivation


memory memory Naive

effector


29 Croft (2010) 29



Leishmania major


OX40L acute



OX40-- acute




93

mCMV acute phase

OX40-- acute

Normal response


J Immunol 2007 Aug 15179(4)2195-202

mCMV chronic phase

OX40--

chronic


VSV OX40-- OX40L--

acute

Normal clearance




OX40-- acute



acute

Normal clearance





Immunity 1999 Dec11(6)699-708


Defective response



Mycobacterium avium

OX40L acute

Normal clearance





30

ProtozoaNematode

Virus

Bacteria


31






Atopic dermatitis

Psoriasis

Healthy control

Healthy control


Lupus nephritis

Ilves et al

Dolff et al

Souza et al

Patschan et al

SLE

IBD

CD3+ OX40+ CD4+ OX40+


Giacomelli et al

OX40 flow cytometry

Colon

Peripheral blood


32



OX

40

L

OX

40

T

C

R

OX

40

LOKT3

T-cell

OX

40

-Fc

OX

40

-Fc

OX

40

-Fc

OX

40

L

OX

40

L

OX

40

L

-4 -3 -2 -1 0 1 200

05

10


GBR 830

No Ab


OD

(450n

m)

10 10 1 01 001

0

50

100

Isotype control

GBR 830


Inh

ibit

ion

of

pro

life

rati

on

(

)

-8 -6 -4 -2 0 2 4-10

-5

0

5

10

15

20IgG1 control

GBR 830

GBR 830-IgG4hs


Sp

ecif

ic A

DC

C (

)

Readout Killing

NK cell

T-cell


33



effe

ctor

effe

ctor+

targ

et

Isoty

pe co

ntrol (

50ugm

L)

Efaliz

umab

(20u

gml)

Efaliz

umab

(2ugm

l)

Efaliz

umab

(00

2ugm

l)

(50u

gml)

(5ugm

l)

(05

ml)

(00

5ugm

l)

(00

1ugm

l)

(00

01ugm

l)

0

2000

4000

6000

3H

in

co

po

rati

on

(re

lati

ve p

roli

fera

tio

n)

OX40 antagonist


34


Treatment

0 20 40 600

50

100 Vehicle

Enbrel (8mgkg)



days

Perc

en

t su

rviv

al



35











36




Iso

typ

e

con

tro

l G

BR

83

0

Tem

ova

te

Donor 1-5

Isoty

pe co

ntrol

GBR83

0

Temova

te

0

50

100

150

200

250

Ep

iderm

al

thic

kn

ess (

m)

Donor 1 Donor 4

Iso

typ

e

con

tro

l G

BR

83

0

Tem

ova

te



37


Bispecific Antibody



Master-Cell Banking





38



39



Bispecific Antibody



Master-Cell Banking







40



CD3+ T cell

HER2+ Tumour Cell

41



cell line



42

0

20

40

60

80

100

No Ab

Ctrl BEAT

CD3 x Her2

Concentration (pM)

o

f s

pec

ific

kil

lin

g




43

44



45

Thank You


10

TL1A (TNFSF15)









receptor)



N C

11


12


X

X

X

13



TL1A


Asthma

Multiple sclerosis

(EAE)

Psoriasis





Friel







Selected

References

COPD


atherosclerosis

15





Bowel Dis 2009)


16



0 5 12

-1 0 +1 +2 +3 +4

16



mucus



Ab 50ug ip


17


F480

F480

TL

1A

T

L1

A Naive mouse

Mouse with UC


18


Siglec F PE

CD

11c

AP

C

Siglec F-PE


Eosinophils





19


IL-12 + IL18 - + + + + + +


5G6 (μgml) - - - 10 1 01 -





IC Monocyte

Mb TL1A

T cell

DR3

IFNg

IFNg

IFNg

IFNg

IFNg

IFNg

IFNg



soluble TL1A

T cell

DR3

IFNg

IFNg

IFNg

IFNg

IFNg

IFNg

IFNg

20


Contr

ol iso

Dex

amet

hasone

GBR91

0 (5

0mgk

g)

Nai

ve

00

2000000

4000000

6000000

8000000

nu

mb

er

of

eo

sin

op

hil

s

Her

ceptin

(20m

gkg)

Cyc

losp

orin

5G6

(20m

gkg)

No

DSS

5

6

7

8

colo

n l

eng

th (

cm

)


DSS colitis

OVA-induced asthma

21

Day -1


- Adhesion

- Strictures

- Ulcers

- Wall thickness

- HampE

- PAS

N=8


Body weight

Day 0



Group3 GBR910

Group4 Prednisolone

starvation

+2 hours Day 7

treatment

Colon length

Histology


22

00

05

10

15

20

25

30

35


AV

ER

AG

E C

OLO

NIC

SC

OR

E

COLONIC PARAMETER




23




In vitro activity







24


25






26


27


OX40 (active homo-

trimer)


Activated T-Cell





C D28 signals

memory memory

Naive

Effector


Memory generation



28


OX40 (active homo-

trimer)


Activated T-Cell






Smaller memory pool

Contraction sooner


Weaker reactivation


memory memory Naive

effector


29 Croft (2010) 29



Leishmania major


OX40L acute



OX40-- acute




93

mCMV acute phase

OX40-- acute

Normal response


J Immunol 2007 Aug 15179(4)2195-202

mCMV chronic phase

OX40--

chronic


VSV OX40-- OX40L--

acute

Normal clearance




OX40-- acute



acute

Normal clearance





Immunity 1999 Dec11(6)699-708


Defective response



Mycobacterium avium

OX40L acute

Normal clearance





30

ProtozoaNematode

Virus

Bacteria


31






Atopic dermatitis

Psoriasis

Healthy control

Healthy control


Lupus nephritis

Ilves et al

Dolff et al

Souza et al

Patschan et al

SLE

IBD

CD3+ OX40+ CD4+ OX40+


Giacomelli et al

OX40 flow cytometry

Colon

Peripheral blood


32



OX

40

L

OX

40

T

C

R

OX

40

LOKT3

T-cell

OX

40

-Fc

OX

40

-Fc

OX

40

-Fc

OX

40

L

OX

40

L

OX

40

L

-4 -3 -2 -1 0 1 200

05

10


GBR 830

No Ab


OD

(450n

m)

10 10 1 01 001

0

50

100

Isotype control

GBR 830


Inh

ibit

ion

of

pro

life

rati

on

(

)

-8 -6 -4 -2 0 2 4-10

-5

0

5

10

15

20IgG1 control

GBR 830

GBR 830-IgG4hs


Sp

ecif

ic A

DC

C (

)

Readout Killing

NK cell

T-cell


33



effe

ctor

effe

ctor+

targ

et

Isoty

pe co

ntrol (

50ugm

L)

Efaliz

umab

(20u

gml)

Efaliz

umab

(2ugm

l)

Efaliz

umab

(00

2ugm

l)

(50u

gml)

(5ugm

l)

(05

ml)

(00

5ugm

l)

(00

1ugm

l)

(00

01ugm

l)

0

2000

4000

6000

3H

in

co

po

rati

on

(re

lati

ve p

roli

fera

tio

n)

OX40 antagonist


34


Treatment

0 20 40 600

50

100 Vehicle

Enbrel (8mgkg)



days

Perc

en

t su

rviv

al



35











36




Iso

typ

e

con

tro

l G

BR

83

0

Tem

ova

te

Donor 1-5

Isoty

pe co

ntrol

GBR83

0

Temova

te

0

50

100

150

200

250

Ep

iderm

al

thic

kn

ess (

m)

Donor 1 Donor 4

Iso

typ

e

con

tro

l G

BR

83

0

Tem

ova

te



37


Bispecific Antibody



Master-Cell Banking





38



39



Bispecific Antibody



Master-Cell Banking







40



CD3+ T cell

HER2+ Tumour Cell

41



cell line



42

0

20

40

60

80

100

No Ab

Ctrl BEAT

CD3 x Her2

Concentration (pM)

o

f s

pec

ific

kil

lin

g




43

44



45

Thank You

TL1A (TNFSF15)









receptor)



N C

11


12


X

X

X

13



TL1A


Asthma

Multiple sclerosis

(EAE)

Psoriasis





Friel







Selected

References

COPD


atherosclerosis

15





Bowel Dis 2009)


16



0 5 12

-1 0 +1 +2 +3 +4

16



mucus



Ab 50ug ip


17


F480

F480

TL

1A

T

L1

A Naive mouse

Mouse with UC


18


Siglec F PE

CD

11c

AP

C

Siglec F-PE


Eosinophils





19


IL-12 + IL18 - + + + + + +


5G6 (μgml) - - - 10 1 01 -





IC Monocyte

Mb TL1A

T cell

DR3

IFNg

IFNg

IFNg

IFNg

IFNg

IFNg

IFNg



soluble TL1A

T cell

DR3

IFNg

IFNg

IFNg

IFNg

IFNg

IFNg

IFNg

20


Contr

ol iso

Dex

amet

hasone

GBR91

0 (5

0mgk

g)

Nai

ve

00

2000000

4000000

6000000

8000000

nu

mb

er

of

eo

sin

op

hil

s

Her

ceptin

(20m

gkg)

Cyc

losp

orin

5G6

(20m

gkg)

No

DSS

5

6

7

8

colo

n l

eng

th (

cm

)


DSS colitis

OVA-induced asthma

21

Day -1


- Adhesion

- Strictures

- Ulcers

- Wall thickness

- HampE

- PAS

N=8


Body weight

Day 0



Group3 GBR910

Group4 Prednisolone

starvation

+2 hours Day 7

treatment

Colon length

Histology


22

00

05

10

15

20

25

30

35


AV

ER

AG

E C

OLO

NIC

SC

OR

E

COLONIC PARAMETER




23




In vitro activity







24


25






26


27


OX40 (active homo-

trimer)


Activated T-Cell





C D28 signals

memory memory

Naive

Effector


Memory generation



28


OX40 (active homo-

trimer)


Activated T-Cell






Smaller memory pool

Contraction sooner


Weaker reactivation


memory memory Naive

effector


29 Croft (2010) 29



Leishmania major


OX40L acute



OX40-- acute




93

mCMV acute phase

OX40-- acute

Normal response


J Immunol 2007 Aug 15179(4)2195-202

mCMV chronic phase

OX40--

chronic


VSV OX40-- OX40L--

acute

Normal clearance




OX40-- acute



acute

Normal clearance





Immunity 1999 Dec11(6)699-708


Defective response



Mycobacterium avium

OX40L acute

Normal clearance





30

ProtozoaNematode

Virus

Bacteria


31






Atopic dermatitis

Psoriasis

Healthy control

Healthy control


Lupus nephritis

Ilves et al

Dolff et al

Souza et al

Patschan et al

SLE

IBD

CD3+ OX40+ CD4+ OX40+


Giacomelli et al

OX40 flow cytometry

Colon

Peripheral blood


32



OX

40

L

OX

40

T

C

R

OX

40

LOKT3

T-cell

OX

40

-Fc

OX

40

-Fc

OX

40

-Fc

OX

40

L

OX

40

L

OX

40

L

-4 -3 -2 -1 0 1 200

05

10


GBR 830

No Ab


OD

(450n

m)

10 10 1 01 001

0

50

100

Isotype control

GBR 830


Inh

ibit

ion

of

pro

life

rati

on

(

)

-8 -6 -4 -2 0 2 4-10

-5

0

5

10

15

20IgG1 control

GBR 830

GBR 830-IgG4hs


Sp

ecif

ic A

DC

C (

)

Readout Killing

NK cell

T-cell


33



effe

ctor

effe

ctor+

targ

et

Isoty

pe co

ntrol (

50ugm

L)

Efaliz

umab

(20u

gml)

Efaliz

umab

(2ugm

l)

Efaliz

umab

(00

2ugm

l)

(50u

gml)

(5ugm

l)

(05

ml)

(00

5ugm

l)

(00

1ugm

l)

(00

01ugm

l)

0

2000

4000

6000

3H

in

co

po

rati

on

(re

lati

ve p

roli

fera

tio

n)

OX40 antagonist


34


Treatment

0 20 40 600

50

100 Vehicle

Enbrel (8mgkg)



days

Perc

en

t su

rviv

al



35











36




Iso

typ

e

con

tro

l G

BR

83

0

Tem

ova

te

Donor 1-5

Isoty

pe co

ntrol

GBR83

0

Temova

te

0

50

100

150

200

250

Ep

iderm

al

thic

kn

ess (

m)

Donor 1 Donor 4

Iso

typ

e

con

tro

l G

BR

83

0

Tem

ova

te



37


Bispecific Antibody



Master-Cell Banking





38



39



Bispecific Antibody



Master-Cell Banking







40



CD3+ T cell

HER2+ Tumour Cell

41



cell line



42

0

20

40

60

80

100

No Ab

Ctrl BEAT

CD3 x Her2

Concentration (pM)

o

f s

pec

ific

kil

lin

g




43

44



45

Thank You


12


X

X

X

13



TL1A


Asthma

Multiple sclerosis

(EAE)

Psoriasis





Friel







Selected

References

COPD


atherosclerosis

15





Bowel Dis 2009)


16



0 5 12

-1 0 +1 +2 +3 +4

16



mucus



Ab 50ug ip


17


F480

F480

TL

1A

T

L1

A Naive mouse

Mouse with UC


18


Siglec F PE

CD

11c

AP

C

Siglec F-PE


Eosinophils





19


IL-12 + IL18 - + + + + + +


5G6 (μgml) - - - 10 1 01 -





IC Monocyte

Mb TL1A

T cell

DR3

IFNg

IFNg

IFNg

IFNg

IFNg

IFNg

IFNg



soluble TL1A

T cell

DR3

IFNg

IFNg

IFNg

IFNg

IFNg

IFNg

IFNg

20


Contr

ol iso

Dex

amet

hasone

GBR91

0 (5

0mgk

g)

Nai

ve

00

2000000

4000000

6000000

8000000

nu

mb

er

of

eo

sin

op

hil

s

Her

ceptin

(20m

gkg)

Cyc

losp

orin

5G6

(20m

gkg)

No

DSS

5

6

7

8

colo

n l

eng

th (

cm

)


DSS colitis

OVA-induced asthma

21

Day -1


- Adhesion

- Strictures

- Ulcers

- Wall thickness

- HampE

- PAS

N=8


Body weight

Day 0



Group3 GBR910

Group4 Prednisolone

starvation

+2 hours Day 7

treatment

Colon length

Histology


22

00

05

10

15

20

25

30

35


AV

ER

AG

E C

OLO

NIC

SC

OR

E

COLONIC PARAMETER




23




In vitro activity







24


25






26


27


OX40 (active homo-

trimer)


Activated T-Cell





C D28 signals

memory memory

Naive

Effector


Memory generation



28


OX40 (active homo-

trimer)


Activated T-Cell






Smaller memory pool

Contraction sooner


Weaker reactivation


memory memory Naive

effector


29 Croft (2010) 29



Leishmania major


OX40L acute



OX40-- acute




93

mCMV acute phase

OX40-- acute

Normal response


J Immunol 2007 Aug 15179(4)2195-202

mCMV chronic phase

OX40--

chronic


VSV OX40-- OX40L--

acute

Normal clearance




OX40-- acute



acute

Normal clearance





Immunity 1999 Dec11(6)699-708


Defective response



Mycobacterium avium

OX40L acute

Normal clearance





30

ProtozoaNematode

Virus

Bacteria


31






Atopic dermatitis

Psoriasis

Healthy control

Healthy control


Lupus nephritis

Ilves et al

Dolff et al

Souza et al

Patschan et al

SLE

IBD

CD3+ OX40+ CD4+ OX40+


Giacomelli et al

OX40 flow cytometry

Colon

Peripheral blood


32



OX

40

L

OX

40

T

C

R

OX

40

LOKT3

T-cell

OX

40

-Fc

OX

40

-Fc

OX

40

-Fc

OX

40

L

OX

40

L

OX

40

L

-4 -3 -2 -1 0 1 200

05

10


GBR 830

No Ab


OD

(450n

m)

10 10 1 01 001

0

50

100

Isotype control

GBR 830


Inh

ibit

ion

of

pro

life

rati

on

(

)

-8 -6 -4 -2 0 2 4-10

-5

0

5

10

15

20IgG1 control

GBR 830

GBR 830-IgG4hs


Sp

ecif

ic A

DC

C (

)

Readout Killing

NK cell

T-cell


33



effe

ctor

effe

ctor+

targ

et

Isoty

pe co

ntrol (

50ugm

L)

Efaliz

umab

(20u

gml)

Efaliz

umab

(2ugm

l)

Efaliz

umab

(00

2ugm

l)

(50u

gml)

(5ugm

l)

(05

ml)

(00

5ugm

l)

(00

1ugm

l)

(00

01ugm

l)

0

2000

4000

6000

3H

in

co

po

rati

on

(re

lati

ve p

roli

fera

tio

n)

OX40 antagonist


34


Treatment

0 20 40 600

50

100 Vehicle

Enbrel (8mgkg)



days

Perc

en

t su

rviv

al



35











36




Iso

typ

e

con

tro

l G

BR

83

0

Tem

ova

te

Donor 1-5

Isoty

pe co

ntrol

GBR83

0

Temova

te

0

50

100

150

200

250

Ep

iderm

al

thic

kn

ess (

m)

Donor 1 Donor 4

Iso

typ

e

con

tro

l G

BR

83

0

Tem

ova

te



37


Bispecific Antibody



Master-Cell Banking





38



39



Bispecific Antibody



Master-Cell Banking







40



CD3+ T cell

HER2+ Tumour Cell

41



cell line



42

0

20

40

60

80

100

No Ab

Ctrl BEAT

CD3 x Her2

Concentration (pM)

o

f s

pec

ific

kil

lin

g




43

44



45

Thank You


X

X

X

13



TL1A


Asthma

Multiple sclerosis

(EAE)

Psoriasis





Friel







Selected

References

COPD


atherosclerosis

15





Bowel Dis 2009)


16



0 5 12

-1 0 +1 +2 +3 +4

16



mucus



Ab 50ug ip


17


F480

F480

TL

1A

T

L1

A Naive mouse

Mouse with UC


18


Siglec F PE

CD

11c

AP

C

Siglec F-PE


Eosinophils





19


IL-12 + IL18 - + + + + + +


5G6 (μgml) - - - 10 1 01 -





IC Monocyte

Mb TL1A

T cell

DR3

IFNg

IFNg

IFNg

IFNg

IFNg

IFNg

IFNg



soluble TL1A

T cell

DR3

IFNg

IFNg

IFNg

IFNg

IFNg

IFNg

IFNg

20


Contr

ol iso

Dex

amet

hasone

GBR91

0 (5

0mgk

g)

Nai

ve

00

2000000

4000000

6000000

8000000

nu

mb

er

of

eo

sin

op

hil

s

Her

ceptin

(20m

gkg)

Cyc

losp

orin

5G6

(20m

gkg)

No

DSS

5

6

7

8

colo

n l

eng

th (

cm

)


DSS colitis

OVA-induced asthma

21

Day -1


- Adhesion

- Strictures

- Ulcers

- Wall thickness

- HampE

- PAS

N=8


Body weight

Day 0



Group3 GBR910

Group4 Prednisolone

starvation

+2 hours Day 7

treatment

Colon length

Histology


22

00

05

10

15

20

25

30

35


AV

ER

AG

E C

OLO

NIC

SC

OR

E

COLONIC PARAMETER




23




In vitro activity







24


25






26


27


OX40 (active homo-

trimer)


Activated T-Cell





C D28 signals

memory memory

Naive

Effector


Memory generation



28


OX40 (active homo-

trimer)


Activated T-Cell






Smaller memory pool

Contraction sooner


Weaker reactivation


memory memory Naive

effector


29 Croft (2010) 29



Leishmania major


OX40L acute



OX40-- acute




93

mCMV acute phase

OX40-- acute

Normal response


J Immunol 2007 Aug 15179(4)2195-202

mCMV chronic phase

OX40--

chronic


VSV OX40-- OX40L--

acute

Normal clearance




OX40-- acute



acute

Normal clearance





Immunity 1999 Dec11(6)699-708


Defective response



Mycobacterium avium

OX40L acute

Normal clearance





30

ProtozoaNematode

Virus

Bacteria


31






Atopic dermatitis

Psoriasis

Healthy control

Healthy control


Lupus nephritis

Ilves et al

Dolff et al

Souza et al

Patschan et al

SLE

IBD

CD3+ OX40+ CD4+ OX40+


Giacomelli et al

OX40 flow cytometry

Colon

Peripheral blood


32



OX

40

L

OX

40

T

C

R

OX

40

LOKT3

T-cell

OX

40

-Fc

OX

40

-Fc

OX

40

-Fc

OX

40

L

OX

40

L

OX

40

L

-4 -3 -2 -1 0 1 200

05

10


GBR 830

No Ab


OD

(450n

m)

10 10 1 01 001

0

50

100

Isotype control

GBR 830


Inh

ibit

ion

of

pro

life

rati

on

(

)

-8 -6 -4 -2 0 2 4-10

-5

0

5

10

15

20IgG1 control

GBR 830

GBR 830-IgG4hs


Sp

ecif

ic A

DC

C (

)

Readout Killing

NK cell

T-cell


33



effe

ctor

effe

ctor+

targ

et

Isoty

pe co

ntrol (

50ugm

L)

Efaliz

umab

(20u

gml)

Efaliz

umab

(2ugm

l)

Efaliz

umab

(00

2ugm

l)

(50u

gml)

(5ugm

l)

(05

ml)

(00

5ugm

l)

(00

1ugm

l)

(00

01ugm

l)

0

2000

4000

6000

3H

in

co

po

rati

on

(re

lati

ve p

roli

fera

tio

n)

OX40 antagonist


34


Treatment

0 20 40 600

50

100 Vehicle

Enbrel (8mgkg)



days

Perc

en

t su

rviv

al



35











36




Iso

typ

e

con

tro

l G

BR

83

0

Tem

ova

te

Donor 1-5

Isoty

pe co

ntrol

GBR83

0

Temova

te

0

50

100

150

200

250

Ep

iderm

al

thic

kn

ess (

m)

Donor 1 Donor 4

Iso

typ

e

con

tro

l G

BR

83

0

Tem

ova

te



37


Bispecific Antibody



Master-Cell Banking





38



39



Bispecific Antibody



Master-Cell Banking







40



CD3+ T cell

HER2+ Tumour Cell

41



cell line



42

0

20

40

60

80

100

No Ab

Ctrl BEAT

CD3 x Her2

Concentration (pM)

o

f s

pec

ific

kil

lin

g




43

44



45

Thank You



TL1A


Asthma

Multiple sclerosis

(EAE)

Psoriasis





Friel







Selected

References

COPD


atherosclerosis

15





Bowel Dis 2009)


16



0 5 12

-1 0 +1 +2 +3 +4

16



mucus



Ab 50ug ip


17


F480

F480

TL

1A

T

L1

A Naive mouse

Mouse with UC


18


Siglec F PE

CD

11c

AP

C

Siglec F-PE


Eosinophils





19


IL-12 + IL18 - + + + + + +


5G6 (μgml) - - - 10 1 01 -





IC Monocyte

Mb TL1A

T cell

DR3

IFNg

IFNg

IFNg

IFNg

IFNg

IFNg

IFNg



soluble TL1A

T cell

DR3

IFNg

IFNg

IFNg

IFNg

IFNg

IFNg

IFNg

20


Contr

ol iso

Dex

amet

hasone

GBR91

0 (5

0mgk

g)

Nai

ve

00

2000000

4000000

6000000

8000000

nu

mb

er

of

eo

sin

op

hil

s

Her

ceptin

(20m

gkg)

Cyc

losp

orin

5G6

(20m

gkg)

No

DSS

5

6

7

8

colo

n l

eng

th (

cm

)


DSS colitis

OVA-induced asthma

21

Day -1


- Adhesion

- Strictures

- Ulcers

- Wall thickness

- HampE

- PAS

N=8


Body weight

Day 0



Group3 GBR910

Group4 Prednisolone

starvation

+2 hours Day 7

treatment

Colon length

Histology


22

00

05

10

15

20

25

30

35


AV

ER

AG

E C

OLO

NIC

SC

OR

E

COLONIC PARAMETER




23




In vitro activity







24


25






26


27


OX40 (active homo-

trimer)


Activated T-Cell





C D28 signals

memory memory

Naive

Effector


Memory generation



28


OX40 (active homo-

trimer)


Activated T-Cell






Smaller memory pool

Contraction sooner


Weaker reactivation


memory memory Naive

effector


29 Croft (2010) 29



Leishmania major


OX40L acute



OX40-- acute




93

mCMV acute phase

OX40-- acute

Normal response


J Immunol 2007 Aug 15179(4)2195-202

mCMV chronic phase

OX40--

chronic


VSV OX40-- OX40L--

acute

Normal clearance




OX40-- acute



acute

Normal clearance





Immunity 1999 Dec11(6)699-708


Defective response



Mycobacterium avium

OX40L acute

Normal clearance





30

ProtozoaNematode

Virus

Bacteria


31






Atopic dermatitis

Psoriasis

Healthy control

Healthy control


Lupus nephritis

Ilves et al

Dolff et al

Souza et al

Patschan et al

SLE

IBD

CD3+ OX40+ CD4+ OX40+


Giacomelli et al

OX40 flow cytometry

Colon

Peripheral blood


32



OX

40

L

OX

40

T

C

R

OX

40

LOKT3

T-cell

OX

40

-Fc

OX

40

-Fc

OX

40

-Fc

OX

40

L

OX

40

L

OX

40

L

-4 -3 -2 -1 0 1 200

05

10


GBR 830

No Ab


OD

(450n

m)

10 10 1 01 001

0

50

100

Isotype control

GBR 830


Inh

ibit

ion

of

pro

life

rati

on

(

)

-8 -6 -4 -2 0 2 4-10

-5

0

5

10

15

20IgG1 control

GBR 830

GBR 830-IgG4hs


Sp

ecif

ic A

DC

C (

)

Readout Killing

NK cell

T-cell


33



effe

ctor

effe

ctor+

targ

et

Isoty

pe co

ntrol (

50ugm

L)

Efaliz

umab

(20u

gml)

Efaliz

umab

(2ugm

l)

Efaliz

umab

(00

2ugm

l)

(50u

gml)

(5ugm

l)

(05

ml)

(00

5ugm

l)

(00

1ugm

l)

(00

01ugm

l)

0

2000

4000

6000

3H

in

co

po

rati

on

(re

lati

ve p

roli

fera

tio

n)

OX40 antagonist


34


Treatment

0 20 40 600

50

100 Vehicle

Enbrel (8mgkg)



days

Perc

en

t su

rviv

al



35











36




Iso

typ

e

con

tro

l G

BR

83

0

Tem

ova

te

Donor 1-5

Isoty

pe co

ntrol

GBR83

0

Temova

te

0

50

100

150

200

250

Ep

iderm

al

thic

kn

ess (

m)

Donor 1 Donor 4

Iso

typ

e

con

tro

l G

BR

83

0

Tem

ova

te



37


Bispecific Antibody



Master-Cell Banking





38



39



Bispecific Antibody



Master-Cell Banking







40



CD3+ T cell

HER2+ Tumour Cell

41



cell line



42

0

20

40

60

80

100

No Ab

Ctrl BEAT

CD3 x Her2

Concentration (pM)

o

f s

pec

ific

kil

lin

g




43

44



45

Thank You

TL1A


Asthma

Multiple sclerosis

(EAE)

Psoriasis





Friel







Selected

References

COPD


atherosclerosis

15





Bowel Dis 2009)


16



0 5 12

-1 0 +1 +2 +3 +4

16



mucus



Ab 50ug ip


17


F480

F480

TL

1A

T

L1

A Naive mouse

Mouse with UC


18


Siglec F PE

CD

11c

AP

C

Siglec F-PE


Eosinophils





19


IL-12 + IL18 - + + + + + +


5G6 (μgml) - - - 10 1 01 -





IC Monocyte

Mb TL1A

T cell

DR3

IFNg

IFNg

IFNg

IFNg

IFNg

IFNg

IFNg



soluble TL1A

T cell

DR3

IFNg

IFNg

IFNg

IFNg

IFNg

IFNg

IFNg

20


Contr

ol iso

Dex

amet

hasone

GBR91

0 (5

0mgk

g)

Nai

ve

00

2000000

4000000

6000000

8000000

nu

mb

er

of

eo

sin

op

hil

s

Her

ceptin

(20m

gkg)

Cyc

losp

orin

5G6

(20m

gkg)

No

DSS

5

6

7

8

colo

n l

eng

th (

cm

)


DSS colitis

OVA-induced asthma

21

Day -1


- Adhesion

- Strictures

- Ulcers

- Wall thickness

- HampE

- PAS

N=8


Body weight

Day 0



Group3 GBR910

Group4 Prednisolone

starvation

+2 hours Day 7

treatment

Colon length

Histology


22

00

05

10

15

20

25

30

35


AV

ER

AG

E C

OLO

NIC

SC

OR

E

COLONIC PARAMETER




23




In vitro activity







24


25






26


27


OX40 (active homo-

trimer)


Activated T-Cell





C D28 signals

memory memory

Naive

Effector


Memory generation



28


OX40 (active homo-

trimer)


Activated T-Cell






Smaller memory pool

Contraction sooner


Weaker reactivation


memory memory Naive

effector


29 Croft (2010) 29



Leishmania major


OX40L acute



OX40-- acute




93

mCMV acute phase

OX40-- acute

Normal response


J Immunol 2007 Aug 15179(4)2195-202

mCMV chronic phase

OX40--

chronic


VSV OX40-- OX40L--

acute

Normal clearance




OX40-- acute



acute

Normal clearance





Immunity 1999 Dec11(6)699-708


Defective response



Mycobacterium avium

OX40L acute

Normal clearance





30

ProtozoaNematode

Virus

Bacteria


31






Atopic dermatitis

Psoriasis

Healthy control

Healthy control


Lupus nephritis

Ilves et al

Dolff et al

Souza et al

Patschan et al

SLE

IBD

CD3+ OX40+ CD4+ OX40+


Giacomelli et al

OX40 flow cytometry

Colon

Peripheral blood


32



OX

40

L

OX

40

T

C

R

OX

40

LOKT3

T-cell

OX

40

-Fc

OX

40

-Fc

OX

40

-Fc

OX

40

L

OX

40

L

OX

40

L

-4 -3 -2 -1 0 1 200

05

10


GBR 830

No Ab


OD

(450n

m)

10 10 1 01 001

0

50

100

Isotype control

GBR 830


Inh

ibit

ion

of

pro

life

rati

on

(

)

-8 -6 -4 -2 0 2 4-10

-5

0

5

10

15

20IgG1 control

GBR 830

GBR 830-IgG4hs


Sp

ecif

ic A

DC

C (

)

Readout Killing

NK cell

T-cell


33



effe

ctor

effe

ctor+

targ

et

Isoty

pe co

ntrol (

50ugm

L)

Efaliz

umab

(20u

gml)

Efaliz

umab

(2ugm

l)

Efaliz

umab

(00

2ugm

l)

(50u

gml)

(5ugm

l)

(05

ml)

(00

5ugm

l)

(00

1ugm

l)

(00

01ugm

l)

0

2000

4000

6000

3H

in

co

po

rati

on

(re

lati

ve p

roli

fera

tio

n)

OX40 antagonist


34


Treatment

0 20 40 600

50

100 Vehicle

Enbrel (8mgkg)



days

Perc

en

t su

rviv

al



35











36




Iso

typ

e

con

tro

l G

BR

83

0

Tem

ova

te

Donor 1-5

Isoty

pe co

ntrol

GBR83

0

Temova

te

0

50

100

150

200

250

Ep

iderm

al

thic

kn

ess (

m)

Donor 1 Donor 4

Iso

typ

e

con

tro

l G

BR

83

0

Tem

ova

te



37


Bispecific Antibody



Master-Cell Banking





38



39



Bispecific Antibody



Master-Cell Banking







40



CD3+ T cell

HER2+ Tumour Cell

41



cell line



42

0

20

40

60

80

100

No Ab

Ctrl BEAT

CD3 x Her2

Concentration (pM)

o

f s

pec

ific

kil

lin

g




43

44



45

Thank You





Bowel Dis 2009)


16



0 5 12

-1 0 +1 +2 +3 +4

16



mucus



Ab 50ug ip


17


F480

F480

TL

1A

T

L1

A Naive mouse

Mouse with UC


18


Siglec F PE

CD

11c

AP

C

Siglec F-PE


Eosinophils





19


IL-12 + IL18 - + + + + + +


5G6 (μgml) - - - 10 1 01 -





IC Monocyte

Mb TL1A

T cell

DR3

IFNg

IFNg

IFNg

IFNg

IFNg

IFNg

IFNg



soluble TL1A

T cell

DR3

IFNg

IFNg

IFNg

IFNg

IFNg

IFNg

IFNg

20


Contr

ol iso

Dex

amet

hasone

GBR91

0 (5

0mgk

g)

Nai

ve

00

2000000

4000000

6000000

8000000

nu

mb

er

of

eo

sin

op

hil

s

Her

ceptin

(20m

gkg)

Cyc

losp

orin

5G6

(20m

gkg)

No

DSS

5

6

7

8

colo

n l

eng

th (

cm

)


DSS colitis

OVA-induced asthma

21

Day -1


- Adhesion

- Strictures

- Ulcers

- Wall thickness

- HampE

- PAS

N=8


Body weight

Day 0



Group3 GBR910

Group4 Prednisolone

starvation

+2 hours Day 7

treatment

Colon length

Histology


22

00

05

10

15

20

25

30

35


AV

ER

AG

E C

OLO

NIC

SC

OR

E

COLONIC PARAMETER




23




In vitro activity







24


25






26


27


OX40 (active homo-

trimer)


Activated T-Cell





C D28 signals

memory memory

Naive

Effector


Memory generation



28


OX40 (active homo-

trimer)


Activated T-Cell






Smaller memory pool

Contraction sooner


Weaker reactivation


memory memory Naive

effector


29 Croft (2010) 29



Leishmania major


OX40L acute



OX40-- acute




93

mCMV acute phase

OX40-- acute

Normal response


J Immunol 2007 Aug 15179(4)2195-202

mCMV chronic phase

OX40--

chronic


VSV OX40-- OX40L--

acute

Normal clearance




OX40-- acute



acute

Normal clearance





Immunity 1999 Dec11(6)699-708


Defective response



Mycobacterium avium

OX40L acute

Normal clearance





30

ProtozoaNematode

Virus

Bacteria


31






Atopic dermatitis

Psoriasis

Healthy control

Healthy control


Lupus nephritis

Ilves et al

Dolff et al

Souza et al

Patschan et al

SLE

IBD

CD3+ OX40+ CD4+ OX40+


Giacomelli et al

OX40 flow cytometry

Colon

Peripheral blood


32



OX

40

L

OX

40

T

C

R

OX

40

LOKT3

T-cell

OX

40

-Fc

OX

40

-Fc

OX

40

-Fc

OX

40

L

OX

40

L

OX

40

L

-4 -3 -2 -1 0 1 200

05

10


GBR 830

No Ab


OD

(450n

m)

10 10 1 01 001

0

50

100

Isotype control

GBR 830


Inh

ibit

ion

of

pro

life

rati

on

(

)

-8 -6 -4 -2 0 2 4-10

-5

0

5

10

15

20IgG1 control

GBR 830

GBR 830-IgG4hs


Sp

ecif

ic A

DC

C (

)

Readout Killing

NK cell

T-cell


33



effe

ctor

effe

ctor+

targ

et

Isoty

pe co

ntrol (

50ugm

L)

Efaliz

umab

(20u

gml)

Efaliz

umab

(2ugm

l)

Efaliz

umab

(00

2ugm

l)

(50u

gml)

(5ugm

l)

(05

ml)

(00

5ugm

l)

(00

1ugm

l)

(00

01ugm

l)

0

2000

4000

6000

3H

in

co

po

rati

on

(re

lati

ve p

roli

fera

tio

n)

OX40 antagonist


34


Treatment

0 20 40 600

50

100 Vehicle

Enbrel (8mgkg)



days

Perc

en

t su

rviv

al



35











36




Iso

typ

e

con

tro

l G

BR

83

0

Tem

ova

te

Donor 1-5

Isoty

pe co

ntrol

GBR83

0

Temova

te

0

50

100

150

200

250

Ep

iderm

al

thic

kn

ess (

m)

Donor 1 Donor 4

Iso

typ

e

con

tro

l G

BR

83

0

Tem

ova

te



37


Bispecific Antibody



Master-Cell Banking





38



39



Bispecific Antibody



Master-Cell Banking







40



CD3+ T cell

HER2+ Tumour Cell

41



cell line



42

0

20

40

60

80

100

No Ab

Ctrl BEAT

CD3 x Her2

Concentration (pM)

o

f s

pec

ific

kil

lin

g




43

44



45

Thank You



0 5 12

-1 0 +1 +2 +3 +4

16



mucus



Ab 50ug ip


17


F480

F480

TL

1A

T

L1

A Naive mouse

Mouse with UC


18


Siglec F PE

CD

11c

AP

C

Siglec F-PE


Eosinophils





19


IL-12 + IL18 - + + + + + +


5G6 (μgml) - - - 10 1 01 -





IC Monocyte

Mb TL1A

T cell

DR3

IFNg

IFNg

IFNg

IFNg

IFNg

IFNg

IFNg



soluble TL1A

T cell

DR3

IFNg

IFNg

IFNg

IFNg

IFNg

IFNg

IFNg

20


Contr

ol iso

Dex

amet

hasone

GBR91

0 (5

0mgk

g)

Nai

ve

00

2000000

4000000

6000000

8000000

nu

mb

er

of

eo

sin

op

hil

s

Her

ceptin

(20m

gkg)

Cyc

losp

orin

5G6

(20m

gkg)

No

DSS

5

6

7

8

colo

n l

eng

th (

cm

)


DSS colitis

OVA-induced asthma

21

Day -1


- Adhesion

- Strictures

- Ulcers

- Wall thickness

- HampE

- PAS

N=8


Body weight

Day 0



Group3 GBR910

Group4 Prednisolone

starvation

+2 hours Day 7

treatment

Colon length

Histology


22

00

05

10

15

20

25

30

35


AV

ER

AG

E C

OLO

NIC

SC

OR

E

COLONIC PARAMETER




23




In vitro activity







24


25






26


27


OX40 (active homo-

trimer)


Activated T-Cell





C D28 signals

memory memory

Naive

Effector


Memory generation



28


OX40 (active homo-

trimer)


Activated T-Cell






Smaller memory pool

Contraction sooner


Weaker reactivation


memory memory Naive

effector


29 Croft (2010) 29



Leishmania major


OX40L acute



OX40-- acute




93

mCMV acute phase

OX40-- acute

Normal response


J Immunol 2007 Aug 15179(4)2195-202

mCMV chronic phase

OX40--

chronic


VSV OX40-- OX40L--

acute

Normal clearance




OX40-- acute



acute

Normal clearance





Immunity 1999 Dec11(6)699-708


Defective response



Mycobacterium avium

OX40L acute

Normal clearance





30

ProtozoaNematode

Virus

Bacteria


31






Atopic dermatitis

Psoriasis

Healthy control

Healthy control


Lupus nephritis

Ilves et al

Dolff et al

Souza et al

Patschan et al

SLE

IBD

CD3+ OX40+ CD4+ OX40+


Giacomelli et al

OX40 flow cytometry

Colon

Peripheral blood


32



OX

40

L

OX

40

T

C

R

OX

40

LOKT3

T-cell

OX

40

-Fc

OX

40

-Fc

OX

40

-Fc

OX

40

L

OX

40

L

OX

40

L

-4 -3 -2 -1 0 1 200

05

10


GBR 830

No Ab


OD

(450n

m)

10 10 1 01 001

0

50

100

Isotype control

GBR 830


Inh

ibit

ion

of

pro

life

rati

on

(

)

-8 -6 -4 -2 0 2 4-10

-5

0

5

10

15

20IgG1 control

GBR 830

GBR 830-IgG4hs


Sp

ecif

ic A

DC

C (

)

Readout Killing

NK cell

T-cell


33



effe

ctor

effe

ctor+

targ

et

Isoty

pe co

ntrol (

50ugm

L)

Efaliz

umab

(20u

gml)

Efaliz

umab

(2ugm

l)

Efaliz

umab

(00

2ugm

l)

(50u

gml)

(5ugm

l)

(05

ml)

(00

5ugm

l)

(00

1ugm

l)

(00

01ugm

l)

0

2000

4000

6000

3H

in

co

po

rati

on

(re

lati

ve p

roli

fera

tio

n)

OX40 antagonist


34


Treatment

0 20 40 600

50

100 Vehicle

Enbrel (8mgkg)



days

Perc

en

t su

rviv

al



35











36




Iso

typ

e

con

tro

l G

BR

83

0

Tem

ova

te

Donor 1-5

Isoty

pe co

ntrol

GBR83

0

Temova

te

0

50

100

150

200

250

Ep

iderm

al

thic

kn

ess (

m)

Donor 1 Donor 4

Iso

typ

e

con

tro

l G

BR

83

0

Tem

ova

te



37


Bispecific Antibody



Master-Cell Banking





38



39



Bispecific Antibody



Master-Cell Banking







40



CD3+ T cell

HER2+ Tumour Cell

41



cell line



42

0

20

40

60

80

100

No Ab

Ctrl BEAT

CD3 x Her2

Concentration (pM)

o

f s

pec

ific

kil

lin

g




43

44



45

Thank You


F480

F480

TL

1A

T

L1

A Naive mouse

Mouse with UC


18


Siglec F PE

CD

11c

AP

C

Siglec F-PE


Eosinophils





19


IL-12 + IL18 - + + + + + +


5G6 (μgml) - - - 10 1 01 -





IC Monocyte

Mb TL1A

T cell

DR3

IFNg

IFNg

IFNg

IFNg

IFNg

IFNg

IFNg



soluble TL1A

T cell

DR3

IFNg

IFNg

IFNg

IFNg

IFNg

IFNg

IFNg

20


Contr

ol iso

Dex

amet

hasone

GBR91

0 (5

0mgk

g)

Nai

ve

00

2000000

4000000

6000000

8000000

nu

mb

er

of

eo

sin

op

hil

s

Her

ceptin

(20m

gkg)

Cyc

losp

orin

5G6

(20m

gkg)

No

DSS

5

6

7

8

colo

n l

eng

th (

cm

)


DSS colitis

OVA-induced asthma

21

Day -1


- Adhesion

- Strictures

- Ulcers

- Wall thickness

- HampE

- PAS

N=8


Body weight

Day 0



Group3 GBR910

Group4 Prednisolone

starvation

+2 hours Day 7

treatment

Colon length

Histology


22

00

05

10

15

20

25

30

35


AV

ER

AG

E C

OLO

NIC

SC

OR

E

COLONIC PARAMETER




23




In vitro activity







24


25






26


27


OX40 (active homo-

trimer)


Activated T-Cell





C D28 signals

memory memory

Naive

Effector


Memory generation



28


OX40 (active homo-

trimer)


Activated T-Cell






Smaller memory pool

Contraction sooner


Weaker reactivation


memory memory Naive

effector


29 Croft (2010) 29



Leishmania major


OX40L acute



OX40-- acute




93

mCMV acute phase

OX40-- acute

Normal response


J Immunol 2007 Aug 15179(4)2195-202

mCMV chronic phase

OX40--

chronic


VSV OX40-- OX40L--

acute

Normal clearance




OX40-- acute



acute

Normal clearance





Immunity 1999 Dec11(6)699-708


Defective response



Mycobacterium avium

OX40L acute

Normal clearance





30

ProtozoaNematode

Virus

Bacteria


31






Atopic dermatitis

Psoriasis

Healthy control

Healthy control


Lupus nephritis

Ilves et al

Dolff et al

Souza et al

Patschan et al

SLE

IBD

CD3+ OX40+ CD4+ OX40+


Giacomelli et al

OX40 flow cytometry

Colon

Peripheral blood


32



OX

40

L

OX

40

T

C

R

OX

40

LOKT3

T-cell

OX

40

-Fc

OX

40

-Fc

OX

40

-Fc

OX

40

L

OX

40

L

OX

40

L

-4 -3 -2 -1 0 1 200

05

10


GBR 830

No Ab


OD

(450n

m)

10 10 1 01 001

0

50

100

Isotype control

GBR 830


Inh

ibit

ion

of

pro

life

rati

on

(

)

-8 -6 -4 -2 0 2 4-10

-5

0

5

10

15

20IgG1 control

GBR 830

GBR 830-IgG4hs


Sp

ecif

ic A

DC

C (

)

Readout Killing

NK cell

T-cell


33



effe

ctor

effe

ctor+

targ

et

Isoty

pe co

ntrol (

50ugm

L)

Efaliz

umab

(20u

gml)

Efaliz

umab

(2ugm

l)

Efaliz

umab

(00

2ugm

l)

(50u

gml)

(5ugm

l)

(05

ml)

(00

5ugm

l)

(00

1ugm

l)

(00

01ugm

l)

0

2000

4000

6000

3H

in

co

po

rati

on

(re

lati

ve p

roli

fera

tio

n)

OX40 antagonist


34


Treatment

0 20 40 600

50

100 Vehicle

Enbrel (8mgkg)



days

Perc

en

t su

rviv

al



35











36




Iso

typ

e

con

tro

l G

BR

83

0

Tem

ova

te

Donor 1-5

Isoty

pe co

ntrol

GBR83

0

Temova

te

0

50

100

150

200

250

Ep

iderm

al

thic

kn

ess (

m)

Donor 1 Donor 4

Iso

typ

e

con

tro

l G

BR

83

0

Tem

ova

te



37


Bispecific Antibody



Master-Cell Banking





38



39



Bispecific Antibody



Master-Cell Banking







40



CD3+ T cell

HER2+ Tumour Cell

41



cell line



42

0

20

40

60

80

100

No Ab

Ctrl BEAT

CD3 x Her2

Concentration (pM)

o

f s

pec

ific

kil

lin

g




43

44



45

Thank You


Siglec F PE

CD

11c

AP

C

Siglec F-PE


Eosinophils





19


IL-12 + IL18 - + + + + + +


5G6 (μgml) - - - 10 1 01 -





IC Monocyte

Mb TL1A

T cell

DR3

IFNg

IFNg

IFNg

IFNg

IFNg

IFNg

IFNg



soluble TL1A

T cell

DR3

IFNg

IFNg

IFNg

IFNg

IFNg

IFNg

IFNg

20


Contr

ol iso

Dex

amet

hasone

GBR91

0 (5

0mgk

g)

Nai

ve

00

2000000

4000000

6000000

8000000

nu

mb

er

of

eo

sin

op

hil

s

Her

ceptin

(20m

gkg)

Cyc

losp

orin

5G6

(20m

gkg)

No

DSS

5

6

7

8

colo

n l

eng

th (

cm

)


DSS colitis

OVA-induced asthma

21

Day -1


- Adhesion

- Strictures

- Ulcers

- Wall thickness

- HampE

- PAS

N=8


Body weight

Day 0



Group3 GBR910

Group4 Prednisolone

starvation

+2 hours Day 7

treatment

Colon length

Histology


22

00

05

10

15

20

25

30

35


AV

ER

AG

E C

OLO

NIC

SC

OR

E

COLONIC PARAMETER




23




In vitro activity







24


25






26


27


OX40 (active homo-

trimer)


Activated T-Cell





C D28 signals

memory memory

Naive

Effector


Memory generation



28


OX40 (active homo-

trimer)


Activated T-Cell






Smaller memory pool

Contraction sooner


Weaker reactivation


memory memory Naive

effector


29 Croft (2010) 29



Leishmania major


OX40L acute



OX40-- acute




93

mCMV acute phase

OX40-- acute

Normal response


J Immunol 2007 Aug 15179(4)2195-202

mCMV chronic phase

OX40--

chronic


VSV OX40-- OX40L--

acute

Normal clearance




OX40-- acute



acute

Normal clearance





Immunity 1999 Dec11(6)699-708


Defective response



Mycobacterium avium

OX40L acute

Normal clearance





30

ProtozoaNematode

Virus

Bacteria


31






Atopic dermatitis

Psoriasis

Healthy control

Healthy control


Lupus nephritis

Ilves et al

Dolff et al

Souza et al

Patschan et al

SLE

IBD

CD3+ OX40+ CD4+ OX40+


Giacomelli et al

OX40 flow cytometry

Colon

Peripheral blood


32



OX

40

L

OX

40

T

C

R

OX

40

LOKT3

T-cell

OX

40

-Fc

OX

40

-Fc

OX

40

-Fc

OX

40

L

OX

40

L

OX

40

L

-4 -3 -2 -1 0 1 200

05

10


GBR 830

No Ab


OD

(450n

m)

10 10 1 01 001

0

50

100

Isotype control

GBR 830


Inh

ibit

ion

of

pro

life

rati

on

(

)

-8 -6 -4 -2 0 2 4-10

-5

0

5

10

15

20IgG1 control

GBR 830

GBR 830-IgG4hs


Sp

ecif

ic A

DC

C (

)

Readout Killing

NK cell

T-cell


33



effe

ctor

effe

ctor+

targ

et

Isoty

pe co

ntrol (

50ugm

L)

Efaliz

umab

(20u

gml)

Efaliz

umab

(2ugm

l)

Efaliz

umab

(00

2ugm

l)

(50u

gml)

(5ugm

l)

(05

ml)

(00

5ugm

l)

(00

1ugm

l)

(00

01ugm

l)

0

2000

4000

6000

3H

in

co

po

rati

on

(re

lati

ve p

roli

fera

tio

n)

OX40 antagonist


34


Treatment

0 20 40 600

50

100 Vehicle

Enbrel (8mgkg)



days

Perc

en

t su

rviv

al



35











36




Iso

typ

e

con

tro

l G

BR

83

0

Tem

ova

te

Donor 1-5

Isoty

pe co

ntrol

GBR83

0

Temova

te

0

50

100

150

200

250

Ep

iderm

al

thic

kn

ess (

m)

Donor 1 Donor 4

Iso

typ

e

con

tro

l G

BR

83

0

Tem

ova

te



37


Bispecific Antibody



Master-Cell Banking





38



39



Bispecific Antibody



Master-Cell Banking







40



CD3+ T cell

HER2+ Tumour Cell

41



cell line



42

0

20

40

60

80

100

No Ab

Ctrl BEAT

CD3 x Her2

Concentration (pM)

o

f s

pec

ific

kil

lin

g




43

44



45

Thank You


IL-12 + IL18 - + + + + + +


5G6 (μgml) - - - 10 1 01 -





IC Monocyte

Mb TL1A

T cell

DR3

IFNg

IFNg

IFNg

IFNg

IFNg

IFNg

IFNg



soluble TL1A

T cell

DR3

IFNg

IFNg

IFNg

IFNg

IFNg

IFNg

IFNg

20


Contr

ol iso

Dex

amet

hasone

GBR91

0 (5

0mgk

g)

Nai

ve

00

2000000

4000000

6000000

8000000

nu

mb

er

of

eo

sin

op

hil

s

Her

ceptin

(20m

gkg)

Cyc

losp

orin

5G6

(20m

gkg)

No

DSS

5

6

7

8

colo

n l

eng

th (

cm

)


DSS colitis

OVA-induced asthma

21

Day -1


- Adhesion

- Strictures

- Ulcers

- Wall thickness

- HampE

- PAS

N=8


Body weight

Day 0



Group3 GBR910

Group4 Prednisolone

starvation

+2 hours Day 7

treatment

Colon length

Histology


22

00

05

10

15

20

25

30

35


AV

ER

AG

E C

OLO

NIC

SC

OR

E

COLONIC PARAMETER




23




In vitro activity







24


25






26


27


OX40 (active homo-

trimer)


Activated T-Cell





C D28 signals

memory memory

Naive

Effector


Memory generation



28


OX40 (active homo-

trimer)


Activated T-Cell






Smaller memory pool

Contraction sooner


Weaker reactivation


memory memory Naive

effector


29 Croft (2010) 29



Leishmania major


OX40L acute



OX40-- acute




93

mCMV acute phase

OX40-- acute

Normal response


J Immunol 2007 Aug 15179(4)2195-202

mCMV chronic phase

OX40--

chronic


VSV OX40-- OX40L--

acute

Normal clearance




OX40-- acute



acute

Normal clearance





Immunity 1999 Dec11(6)699-708


Defective response



Mycobacterium avium

OX40L acute

Normal clearance





30

ProtozoaNematode

Virus

Bacteria


31






Atopic dermatitis

Psoriasis

Healthy control

Healthy control


Lupus nephritis

Ilves et al

Dolff et al

Souza et al

Patschan et al

SLE

IBD

CD3+ OX40+ CD4+ OX40+


Giacomelli et al

OX40 flow cytometry

Colon

Peripheral blood


32



OX

40

L

OX

40

T

C

R

OX

40

LOKT3

T-cell

OX

40

-Fc

OX

40

-Fc

OX

40

-Fc

OX

40

L

OX

40

L

OX

40

L

-4 -3 -2 -1 0 1 200

05

10


GBR 830

No Ab


OD

(450n

m)

10 10 1 01 001

0

50

100

Isotype control

GBR 830


Inh

ibit

ion

of

pro

life

rati

on

(

)

-8 -6 -4 -2 0 2 4-10

-5

0

5

10

15

20IgG1 control

GBR 830

GBR 830-IgG4hs


Sp

ecif

ic A

DC

C (

)

Readout Killing

NK cell

T-cell


33



effe

ctor

effe

ctor+

targ

et

Isoty

pe co

ntrol (

50ugm

L)

Efaliz

umab

(20u

gml)

Efaliz

umab

(2ugm

l)

Efaliz

umab

(00

2ugm

l)

(50u

gml)

(5ugm

l)

(05

ml)

(00

5ugm

l)

(00

1ugm

l)

(00

01ugm

l)

0

2000

4000

6000

3H

in

co

po

rati

on

(re

lati

ve p

roli

fera

tio

n)

OX40 antagonist


34


Treatment

0 20 40 600

50

100 Vehicle

Enbrel (8mgkg)



days

Perc

en

t su

rviv

al



35











36




Iso

typ

e

con

tro

l G

BR

83

0

Tem

ova

te

Donor 1-5

Isoty

pe co

ntrol

GBR83

0

Temova

te

0

50

100

150

200

250

Ep

iderm

al

thic

kn

ess (

m)

Donor 1 Donor 4

Iso

typ

e

con

tro

l G

BR

83

0

Tem

ova

te



37


Bispecific Antibody



Master-Cell Banking





38



39



Bispecific Antibody



Master-Cell Banking







40



CD3+ T cell

HER2+ Tumour Cell

41



cell line



42

0

20

40

60

80

100

No Ab

Ctrl BEAT

CD3 x Her2

Concentration (pM)

o

f s

pec

ific

kil

lin

g




43

44



45

Thank You


Contr

ol iso

Dex

amet

hasone

GBR91

0 (5

0mgk

g)

Nai

ve

00

2000000

4000000

6000000

8000000

nu

mb

er

of

eo

sin

op

hil

s

Her

ceptin

(20m

gkg)

Cyc

losp

orin

5G6

(20m

gkg)

No

DSS

5

6

7

8

colo

n l

eng

th (

cm

)


DSS colitis

OVA-induced asthma

21

Day -1


- Adhesion

- Strictures

- Ulcers

- Wall thickness

- HampE

- PAS

N=8


Body weight

Day 0



Group3 GBR910

Group4 Prednisolone

starvation

+2 hours Day 7

treatment

Colon length

Histology


22

00

05

10

15

20

25

30

35


AV

ER

AG

E C

OLO

NIC

SC

OR

E

COLONIC PARAMETER




23




In vitro activity







24


25






26


27


OX40 (active homo-

trimer)


Activated T-Cell





C D28 signals

memory memory

Naive

Effector


Memory generation



28


OX40 (active homo-

trimer)


Activated T-Cell






Smaller memory pool

Contraction sooner


Weaker reactivation


memory memory Naive

effector


29 Croft (2010) 29



Leishmania major


OX40L acute



OX40-- acute




93

mCMV acute phase

OX40-- acute

Normal response


J Immunol 2007 Aug 15179(4)2195-202

mCMV chronic phase

OX40--

chronic


VSV OX40-- OX40L--

acute

Normal clearance




OX40-- acute



acute

Normal clearance





Immunity 1999 Dec11(6)699-708


Defective response



Mycobacterium avium

OX40L acute

Normal clearance





30

ProtozoaNematode

Virus

Bacteria


31






Atopic dermatitis

Psoriasis

Healthy control

Healthy control


Lupus nephritis

Ilves et al

Dolff et al

Souza et al

Patschan et al

SLE

IBD

CD3+ OX40+ CD4+ OX40+


Giacomelli et al

OX40 flow cytometry

Colon

Peripheral blood


32



OX

40

L

OX

40

T

C

R

OX

40

LOKT3

T-cell

OX

40

-Fc

OX

40

-Fc

OX

40

-Fc

OX

40

L

OX

40

L

OX

40

L

-4 -3 -2 -1 0 1 200

05

10


GBR 830

No Ab


OD

(450n

m)

10 10 1 01 001

0

50

100

Isotype control

GBR 830


Inh

ibit

ion

of

pro

life

rati

on

(

)

-8 -6 -4 -2 0 2 4-10

-5

0

5

10

15

20IgG1 control

GBR 830

GBR 830-IgG4hs


Sp

ecif

ic A

DC

C (

)

Readout Killing

NK cell

T-cell


33



effe

ctor

effe

ctor+

targ

et

Isoty

pe co

ntrol (

50ugm

L)

Efaliz

umab

(20u

gml)

Efaliz

umab

(2ugm

l)

Efaliz

umab

(00

2ugm

l)

(50u

gml)

(5ugm

l)

(05

ml)

(00

5ugm

l)

(00

1ugm

l)

(00

01ugm

l)

0

2000

4000

6000

3H

in

co

po

rati

on

(re

lati

ve p

roli

fera

tio

n)

OX40 antagonist


34


Treatment

0 20 40 600

50

100 Vehicle

Enbrel (8mgkg)



days

Perc

en

t su

rviv

al



35











36




Iso

typ

e

con

tro

l G

BR

83

0

Tem

ova

te

Donor 1-5

Isoty

pe co

ntrol

GBR83

0

Temova

te

0

50

100

150

200

250

Ep

iderm

al

thic

kn

ess (

m)

Donor 1 Donor 4

Iso

typ

e

con

tro

l G

BR

83

0

Tem

ova

te



37


Bispecific Antibody



Master-Cell Banking





38



39



Bispecific Antibody



Master-Cell Banking







40



CD3+ T cell

HER2+ Tumour Cell

41



cell line



42

0

20

40

60

80

100

No Ab

Ctrl BEAT

CD3 x Her2

Concentration (pM)

o

f s

pec

ific

kil

lin

g




43

44



45

Thank You

Day -1


- Adhesion

- Strictures

- Ulcers

- Wall thickness

- HampE

- PAS

N=8


Body weight

Day 0



Group3 GBR910

Group4 Prednisolone

starvation

+2 hours Day 7

treatment

Colon length

Histology


22

00

05

10

15

20

25

30

35


AV

ER

AG

E C

OLO

NIC

SC

OR

E

COLONIC PARAMETER




23




In vitro activity







24


25






26


27


OX40 (active homo-

trimer)


Activated T-Cell





C D28 signals

memory memory

Naive

Effector


Memory generation



28


OX40 (active homo-

trimer)


Activated T-Cell






Smaller memory pool

Contraction sooner


Weaker reactivation


memory memory Naive

effector


29 Croft (2010) 29



Leishmania major


OX40L acute



OX40-- acute




93

mCMV acute phase

OX40-- acute

Normal response


J Immunol 2007 Aug 15179(4)2195-202

mCMV chronic phase

OX40--

chronic


VSV OX40-- OX40L--

acute

Normal clearance




OX40-- acute



acute

Normal clearance





Immunity 1999 Dec11(6)699-708


Defective response



Mycobacterium avium

OX40L acute

Normal clearance





30

ProtozoaNematode

Virus

Bacteria


31






Atopic dermatitis

Psoriasis

Healthy control

Healthy control


Lupus nephritis

Ilves et al

Dolff et al

Souza et al

Patschan et al

SLE

IBD

CD3+ OX40+ CD4+ OX40+


Giacomelli et al

OX40 flow cytometry

Colon

Peripheral blood


32



OX

40

L

OX

40

T

C

R

OX

40

LOKT3

T-cell

OX

40

-Fc

OX

40

-Fc

OX

40

-Fc

OX

40

L

OX

40

L

OX

40

L

-4 -3 -2 -1 0 1 200

05

10


GBR 830

No Ab


OD

(450n

m)

10 10 1 01 001

0

50

100

Isotype control

GBR 830


Inh

ibit

ion

of

pro

life

rati

on

(

)

-8 -6 -4 -2 0 2 4-10

-5

0

5

10

15

20IgG1 control

GBR 830

GBR 830-IgG4hs


Sp

ecif

ic A

DC

C (

)

Readout Killing

NK cell

T-cell


33



effe

ctor

effe

ctor+

targ

et

Isoty

pe co

ntrol (

50ugm

L)

Efaliz

umab

(20u

gml)

Efaliz

umab

(2ugm

l)

Efaliz

umab

(00

2ugm

l)

(50u

gml)

(5ugm

l)

(05

ml)

(00

5ugm

l)

(00

1ugm

l)

(00

01ugm

l)

0

2000

4000

6000

3H

in

co

po

rati

on

(re

lati

ve p

roli

fera

tio

n)

OX40 antagonist


34


Treatment

0 20 40 600

50

100 Vehicle

Enbrel (8mgkg)



days

Perc

en

t su

rviv

al



35











36




Iso

typ

e

con

tro

l G

BR

83

0

Tem

ova

te

Donor 1-5

Isoty

pe co

ntrol

GBR83

0

Temova

te

0

50

100

150

200

250

Ep

iderm

al

thic

kn

ess (

m)

Donor 1 Donor 4

Iso

typ

e

con

tro

l G

BR

83

0

Tem

ova

te



37


Bispecific Antibody



Master-Cell Banking





38



39



Bispecific Antibody



Master-Cell Banking







40



CD3+ T cell

HER2+ Tumour Cell

41



cell line



42

0

20

40

60

80

100

No Ab

Ctrl BEAT

CD3 x Her2

Concentration (pM)

o

f s

pec

ific

kil

lin

g




43

44



45

Thank You

00

05

10

15

20

25

30

35


AV

ER

AG

E C

OLO

NIC

SC

OR

E

COLONIC PARAMETER




23




In vitro activity







24


25






26


27


OX40 (active homo-

trimer)


Activated T-Cell





C D28 signals

memory memory

Naive

Effector


Memory generation



28


OX40 (active homo-

trimer)


Activated T-Cell






Smaller memory pool

Contraction sooner


Weaker reactivation


memory memory Naive

effector


29 Croft (2010) 29



Leishmania major


OX40L acute



OX40-- acute




93

mCMV acute phase

OX40-- acute

Normal response


J Immunol 2007 Aug 15179(4)2195-202

mCMV chronic phase

OX40--

chronic


VSV OX40-- OX40L--

acute

Normal clearance




OX40-- acute



acute

Normal clearance





Immunity 1999 Dec11(6)699-708


Defective response



Mycobacterium avium

OX40L acute

Normal clearance





30

ProtozoaNematode

Virus

Bacteria


31






Atopic dermatitis

Psoriasis

Healthy control

Healthy control


Lupus nephritis

Ilves et al

Dolff et al

Souza et al

Patschan et al

SLE

IBD

CD3+ OX40+ CD4+ OX40+


Giacomelli et al

OX40 flow cytometry

Colon

Peripheral blood


32



OX

40

L

OX

40

T

C

R

OX

40

LOKT3

T-cell

OX

40

-Fc

OX

40

-Fc

OX

40

-Fc

OX

40

L

OX

40

L

OX

40

L

-4 -3 -2 -1 0 1 200

05

10


GBR 830

No Ab


OD

(450n

m)

10 10 1 01 001

0

50

100

Isotype control

GBR 830


Inh

ibit

ion

of

pro

life

rati

on

(

)

-8 -6 -4 -2 0 2 4-10

-5

0

5

10

15

20IgG1 control

GBR 830

GBR 830-IgG4hs


Sp

ecif

ic A

DC

C (

)

Readout Killing

NK cell

T-cell


33



effe

ctor

effe

ctor+

targ

et

Isoty

pe co

ntrol (

50ugm

L)

Efaliz

umab

(20u

gml)

Efaliz

umab

(2ugm

l)

Efaliz

umab

(00

2ugm

l)

(50u

gml)

(5ugm

l)

(05

ml)

(00

5ugm

l)

(00

1ugm

l)

(00

01ugm

l)

0

2000

4000

6000

3H

in

co

po

rati

on

(re

lati

ve p

roli

fera

tio

n)

OX40 antagonist


34


Treatment

0 20 40 600

50

100 Vehicle

Enbrel (8mgkg)



days

Perc

en

t su

rviv

al



35











36




Iso

typ

e

con

tro

l G

BR

83

0

Tem

ova

te

Donor 1-5

Isoty

pe co

ntrol

GBR83

0

Temova

te

0

50

100

150

200

250

Ep

iderm

al

thic

kn

ess (

m)

Donor 1 Donor 4

Iso

typ

e

con

tro

l G

BR

83

0

Tem

ova

te



37


Bispecific Antibody



Master-Cell Banking





38



39



Bispecific Antibody



Master-Cell Banking







40



CD3+ T cell

HER2+ Tumour Cell

41



cell line



42

0

20

40

60

80

100

No Ab

Ctrl BEAT

CD3 x Her2

Concentration (pM)

o

f s

pec

ific

kil

lin

g




43

44



45

Thank You




In vitro activity







24


25






26


27


OX40 (active homo-

trimer)


Activated T-Cell





C D28 signals

memory memory

Naive

Effector


Memory generation



28


OX40 (active homo-

trimer)


Activated T-Cell






Smaller memory pool

Contraction sooner


Weaker reactivation


memory memory Naive

effector


29 Croft (2010) 29



Leishmania major


OX40L acute



OX40-- acute




93

mCMV acute phase

OX40-- acute

Normal response


J Immunol 2007 Aug 15179(4)2195-202

mCMV chronic phase

OX40--

chronic


VSV OX40-- OX40L--

acute

Normal clearance




OX40-- acute



acute

Normal clearance





Immunity 1999 Dec11(6)699-708


Defective response



Mycobacterium avium

OX40L acute

Normal clearance





30

ProtozoaNematode

Virus

Bacteria


31






Atopic dermatitis

Psoriasis

Healthy control

Healthy control


Lupus nephritis

Ilves et al

Dolff et al

Souza et al

Patschan et al

SLE

IBD

CD3+ OX40+ CD4+ OX40+


Giacomelli et al

OX40 flow cytometry

Colon

Peripheral blood


32



OX

40

L

OX

40

T

C

R

OX

40

LOKT3

T-cell

OX

40

-Fc

OX

40

-Fc

OX

40

-Fc

OX

40

L

OX

40

L

OX

40

L

-4 -3 -2 -1 0 1 200

05

10


GBR 830

No Ab


OD

(450n

m)

10 10 1 01 001

0

50

100

Isotype control

GBR 830


Inh

ibit

ion

of

pro

life

rati

on

(

)

-8 -6 -4 -2 0 2 4-10

-5

0

5

10

15

20IgG1 control

GBR 830

GBR 830-IgG4hs


Sp

ecif

ic A

DC

C (

)

Readout Killing

NK cell

T-cell


33



effe

ctor

effe

ctor+

targ

et

Isoty

pe co

ntrol (

50ugm

L)

Efaliz

umab

(20u

gml)

Efaliz

umab

(2ugm

l)

Efaliz

umab

(00

2ugm

l)

(50u

gml)

(5ugm

l)

(05

ml)

(00

5ugm

l)

(00

1ugm

l)

(00

01ugm

l)

0

2000

4000

6000

3H

in

co

po

rati

on

(re

lati

ve p

roli

fera

tio

n)

OX40 antagonist


34


Treatment

0 20 40 600

50

100 Vehicle

Enbrel (8mgkg)



days

Perc

en

t su

rviv

al



35











36




Iso

typ

e

con

tro

l G

BR

83

0

Tem

ova

te

Donor 1-5

Isoty

pe co

ntrol

GBR83

0

Temova

te

0

50

100

150

200

250

Ep

iderm

al

thic

kn

ess (

m)

Donor 1 Donor 4

Iso

typ

e

con

tro

l G

BR

83

0

Tem

ova

te



37


Bispecific Antibody



Master-Cell Banking





38



39



Bispecific Antibody



Master-Cell Banking







40



CD3+ T cell

HER2+ Tumour Cell

41



cell line



42

0

20

40

60

80

100

No Ab

Ctrl BEAT

CD3 x Her2

Concentration (pM)

o

f s

pec

ific

kil

lin

g




43

44



45

Thank You


25






26


27


OX40 (active homo-

trimer)


Activated T-Cell





C D28 signals

memory memory

Naive

Effector


Memory generation



28


OX40 (active homo-

trimer)


Activated T-Cell






Smaller memory pool

Contraction sooner


Weaker reactivation


memory memory Naive

effector


29 Croft (2010) 29



Leishmania major


OX40L acute



OX40-- acute




93

mCMV acute phase

OX40-- acute

Normal response


J Immunol 2007 Aug 15179(4)2195-202

mCMV chronic phase

OX40--

chronic


VSV OX40-- OX40L--

acute

Normal clearance




OX40-- acute



acute

Normal clearance





Immunity 1999 Dec11(6)699-708


Defective response



Mycobacterium avium

OX40L acute

Normal clearance





30

ProtozoaNematode

Virus

Bacteria


31






Atopic dermatitis

Psoriasis

Healthy control

Healthy control


Lupus nephritis

Ilves et al

Dolff et al

Souza et al

Patschan et al

SLE

IBD

CD3+ OX40+ CD4+ OX40+


Giacomelli et al

OX40 flow cytometry

Colon

Peripheral blood


32



OX

40

L

OX

40

T

C

R

OX

40

LOKT3

T-cell

OX

40

-Fc

OX

40

-Fc

OX

40

-Fc

OX

40

L

OX

40

L

OX

40

L

-4 -3 -2 -1 0 1 200

05

10


GBR 830

No Ab


OD

(450n

m)

10 10 1 01 001

0

50

100

Isotype control

GBR 830


Inh

ibit

ion

of

pro

life

rati

on

(

)

-8 -6 -4 -2 0 2 4-10

-5

0

5

10

15

20IgG1 control

GBR 830

GBR 830-IgG4hs


Sp

ecif

ic A

DC

C (

)

Readout Killing

NK cell

T-cell


33



effe

ctor

effe

ctor+

targ

et

Isoty

pe co

ntrol (

50ugm

L)

Efaliz

umab

(20u

gml)

Efaliz

umab

(2ugm

l)

Efaliz

umab

(00

2ugm

l)

(50u

gml)

(5ugm

l)

(05

ml)

(00

5ugm

l)

(00

1ugm

l)

(00

01ugm

l)

0

2000

4000

6000

3H

in

co

po

rati

on

(re

lati

ve p

roli

fera

tio

n)

OX40 antagonist


34


Treatment

0 20 40 600

50

100 Vehicle

Enbrel (8mgkg)



days

Perc

en

t su

rviv

al



35











36




Iso

typ

e

con

tro

l G

BR

83

0

Tem

ova

te

Donor 1-5

Isoty

pe co

ntrol

GBR83

0

Temova

te

0

50

100

150

200

250

Ep

iderm

al

thic

kn

ess (

m)

Donor 1 Donor 4

Iso

typ

e

con

tro

l G

BR

83

0

Tem

ova

te



37


Bispecific Antibody



Master-Cell Banking





38



39



Bispecific Antibody



Master-Cell Banking







40



CD3+ T cell

HER2+ Tumour Cell

41



cell line



42

0

20

40

60

80

100

No Ab

Ctrl BEAT

CD3 x Her2

Concentration (pM)

o

f s

pec

ific

kil

lin

g




43

44



45

Thank You






26


27


OX40 (active homo-

trimer)


Activated T-Cell





C D28 signals

memory memory

Naive

Effector


Memory generation



28


OX40 (active homo-

trimer)


Activated T-Cell






Smaller memory pool

Contraction sooner


Weaker reactivation


memory memory Naive

effector


29 Croft (2010) 29



Leishmania major


OX40L acute



OX40-- acute




93

mCMV acute phase

OX40-- acute

Normal response


J Immunol 2007 Aug 15179(4)2195-202

mCMV chronic phase

OX40--

chronic


VSV OX40-- OX40L--

acute

Normal clearance




OX40-- acute



acute

Normal clearance





Immunity 1999 Dec11(6)699-708


Defective response



Mycobacterium avium

OX40L acute

Normal clearance





30

ProtozoaNematode

Virus

Bacteria


31






Atopic dermatitis

Psoriasis

Healthy control

Healthy control


Lupus nephritis

Ilves et al

Dolff et al

Souza et al

Patschan et al

SLE

IBD

CD3+ OX40+ CD4+ OX40+


Giacomelli et al

OX40 flow cytometry

Colon

Peripheral blood


32



OX

40

L

OX

40

T

C

R

OX

40

LOKT3

T-cell

OX

40

-Fc

OX

40

-Fc

OX

40

-Fc

OX

40

L

OX

40

L

OX

40

L

-4 -3 -2 -1 0 1 200

05

10


GBR 830

No Ab


OD

(450n

m)

10 10 1 01 001

0

50

100

Isotype control

GBR 830


Inh

ibit

ion

of

pro

life

rati

on

(

)

-8 -6 -4 -2 0 2 4-10

-5

0

5

10

15

20IgG1 control

GBR 830

GBR 830-IgG4hs


Sp

ecif

ic A

DC

C (

)

Readout Killing

NK cell

T-cell


33



effe

ctor

effe

ctor+

targ

et

Isoty

pe co

ntrol (

50ugm

L)

Efaliz

umab

(20u

gml)

Efaliz

umab

(2ugm

l)

Efaliz

umab

(00

2ugm

l)

(50u

gml)

(5ugm

l)

(05

ml)

(00

5ugm

l)

(00

1ugm

l)

(00

01ugm

l)

0

2000

4000

6000

3H

in

co

po

rati

on

(re

lati

ve p

roli

fera

tio

n)

OX40 antagonist


34


Treatment

0 20 40 600

50

100 Vehicle

Enbrel (8mgkg)



days

Perc

en

t su

rviv

al



35











36




Iso

typ

e

con

tro

l G

BR

83

0

Tem

ova

te

Donor 1-5

Isoty

pe co

ntrol

GBR83

0

Temova

te

0

50

100

150

200

250

Ep

iderm

al

thic

kn

ess (

m)

Donor 1 Donor 4

Iso

typ

e

con

tro

l G

BR

83

0

Tem

ova

te



37


Bispecific Antibody



Master-Cell Banking





38



39



Bispecific Antibody



Master-Cell Banking







40



CD3+ T cell

HER2+ Tumour Cell

41



cell line



42

0

20

40

60

80

100

No Ab

Ctrl BEAT

CD3 x Her2

Concentration (pM)

o

f s

pec

ific

kil

lin

g




43

44



45

Thank You


27


OX40 (active homo-

trimer)


Activated T-Cell





C D28 signals

memory memory

Naive

Effector


Memory generation



28


OX40 (active homo-

trimer)


Activated T-Cell






Smaller memory pool

Contraction sooner


Weaker reactivation


memory memory Naive

effector


29 Croft (2010) 29



Leishmania major


OX40L acute



OX40-- acute




93

mCMV acute phase

OX40-- acute

Normal response


J Immunol 2007 Aug 15179(4)2195-202

mCMV chronic phase

OX40--

chronic


VSV OX40-- OX40L--

acute

Normal clearance




OX40-- acute



acute

Normal clearance





Immunity 1999 Dec11(6)699-708


Defective response



Mycobacterium avium

OX40L acute

Normal clearance





30

ProtozoaNematode

Virus

Bacteria


31






Atopic dermatitis

Psoriasis

Healthy control

Healthy control


Lupus nephritis

Ilves et al

Dolff et al

Souza et al

Patschan et al

SLE

IBD

CD3+ OX40+ CD4+ OX40+


Giacomelli et al

OX40 flow cytometry

Colon

Peripheral blood


32



OX

40

L

OX

40

T

C

R

OX

40

LOKT3

T-cell

OX

40

-Fc

OX

40

-Fc

OX

40

-Fc

OX

40

L

OX

40

L

OX

40

L

-4 -3 -2 -1 0 1 200

05

10


GBR 830

No Ab


OD

(450n

m)

10 10 1 01 001

0

50

100

Isotype control

GBR 830


Inh

ibit

ion

of

pro

life

rati

on

(

)

-8 -6 -4 -2 0 2 4-10

-5

0

5

10

15

20IgG1 control

GBR 830

GBR 830-IgG4hs


Sp

ecif

ic A

DC

C (

)

Readout Killing

NK cell

T-cell


33



effe

ctor

effe

ctor+

targ

et

Isoty

pe co

ntrol (

50ugm

L)

Efaliz

umab

(20u

gml)

Efaliz

umab

(2ugm

l)

Efaliz

umab

(00

2ugm

l)

(50u

gml)

(5ugm

l)

(05

ml)

(00

5ugm

l)

(00

1ugm

l)

(00

01ugm

l)

0

2000

4000

6000

3H

in

co

po

rati

on

(re

lati

ve p

roli

fera

tio

n)

OX40 antagonist


34


Treatment

0 20 40 600

50

100 Vehicle

Enbrel (8mgkg)



days

Perc

en

t su

rviv

al



35











36




Iso

typ

e

con

tro

l G

BR

83

0

Tem

ova

te

Donor 1-5

Isoty

pe co

ntrol

GBR83

0

Temova

te

0

50

100

150

200

250

Ep

iderm

al

thic

kn

ess (

m)

Donor 1 Donor 4

Iso

typ

e

con

tro

l G

BR

83

0

Tem

ova

te



37


Bispecific Antibody



Master-Cell Banking





38



39



Bispecific Antibody



Master-Cell Banking







40



CD3+ T cell

HER2+ Tumour Cell

41



cell line



42

0

20

40

60

80

100

No Ab

Ctrl BEAT

CD3 x Her2

Concentration (pM)

o

f s

pec

ific

kil

lin

g




43

44



45

Thank You


28


OX40 (active homo-

trimer)


Activated T-Cell






Smaller memory pool

Contraction sooner


Weaker reactivation


memory memory Naive

effector


29 Croft (2010) 29



Leishmania major


OX40L acute



OX40-- acute




93

mCMV acute phase

OX40-- acute

Normal response


J Immunol 2007 Aug 15179(4)2195-202

mCMV chronic phase

OX40--

chronic


VSV OX40-- OX40L--

acute

Normal clearance




OX40-- acute



acute

Normal clearance





Immunity 1999 Dec11(6)699-708


Defective response



Mycobacterium avium

OX40L acute

Normal clearance





30

ProtozoaNematode

Virus

Bacteria


31






Atopic dermatitis

Psoriasis

Healthy control

Healthy control


Lupus nephritis

Ilves et al

Dolff et al

Souza et al

Patschan et al

SLE

IBD

CD3+ OX40+ CD4+ OX40+


Giacomelli et al

OX40 flow cytometry

Colon

Peripheral blood


32



OX

40

L

OX

40

T

C

R

OX

40

LOKT3

T-cell

OX

40

-Fc

OX

40

-Fc

OX

40

-Fc

OX

40

L

OX

40

L

OX

40

L

-4 -3 -2 -1 0 1 200

05

10


GBR 830

No Ab


OD

(450n

m)

10 10 1 01 001

0

50

100

Isotype control

GBR 830


Inh

ibit

ion

of

pro

life

rati

on

(

)

-8 -6 -4 -2 0 2 4-10

-5

0

5

10

15

20IgG1 control

GBR 830

GBR 830-IgG4hs


Sp

ecif

ic A

DC

C (

)

Readout Killing

NK cell

T-cell


33



effe

ctor

effe

ctor+

targ

et

Isoty

pe co

ntrol (

50ugm

L)

Efaliz

umab

(20u

gml)

Efaliz

umab

(2ugm

l)

Efaliz

umab

(00

2ugm

l)

(50u

gml)

(5ugm

l)

(05

ml)

(00

5ugm

l)

(00

1ugm

l)

(00

01ugm

l)

0

2000

4000

6000

3H

in

co

po

rati

on

(re

lati

ve p

roli

fera

tio

n)

OX40 antagonist


34


Treatment

0 20 40 600

50

100 Vehicle

Enbrel (8mgkg)



days

Perc

en

t su

rviv

al



35











36




Iso

typ

e

con

tro

l G

BR

83

0

Tem

ova

te

Donor 1-5

Isoty

pe co

ntrol

GBR83

0

Temova

te

0

50

100

150

200

250

Ep

iderm

al

thic

kn

ess (

m)

Donor 1 Donor 4

Iso

typ

e

con

tro

l G

BR

83

0

Tem

ova

te



37


Bispecific Antibody



Master-Cell Banking





38



39



Bispecific Antibody



Master-Cell Banking







40



CD3+ T cell

HER2+ Tumour Cell

41



cell line



42

0

20

40

60

80

100

No Ab

Ctrl BEAT

CD3 x Her2

Concentration (pM)

o

f s

pec

ific

kil

lin

g




43

44



45

Thank You


29 Croft (2010) 29



Leishmania major


OX40L acute



OX40-- acute




93

mCMV acute phase

OX40-- acute

Normal response


J Immunol 2007 Aug 15179(4)2195-202

mCMV chronic phase

OX40--

chronic


VSV OX40-- OX40L--

acute

Normal clearance




OX40-- acute



acute

Normal clearance





Immunity 1999 Dec11(6)699-708


Defective response



Mycobacterium avium

OX40L acute

Normal clearance





30

ProtozoaNematode

Virus

Bacteria


31






Atopic dermatitis

Psoriasis

Healthy control

Healthy control


Lupus nephritis

Ilves et al

Dolff et al

Souza et al

Patschan et al

SLE

IBD

CD3+ OX40+ CD4+ OX40+


Giacomelli et al

OX40 flow cytometry

Colon

Peripheral blood


32



OX

40

L

OX

40

T

C

R

OX

40

LOKT3

T-cell

OX

40

-Fc

OX

40

-Fc

OX

40

-Fc

OX

40

L

OX

40

L

OX

40

L

-4 -3 -2 -1 0 1 200

05

10


GBR 830

No Ab


OD

(450n

m)

10 10 1 01 001

0

50

100

Isotype control

GBR 830


Inh

ibit

ion

of

pro

life

rati

on

(

)

-8 -6 -4 -2 0 2 4-10

-5

0

5

10

15

20IgG1 control

GBR 830

GBR 830-IgG4hs


Sp

ecif

ic A

DC

C (

)

Readout Killing

NK cell

T-cell


33



effe

ctor

effe

ctor+

targ

et

Isoty

pe co

ntrol (

50ugm

L)

Efaliz

umab

(20u

gml)

Efaliz

umab

(2ugm

l)

Efaliz

umab

(00

2ugm

l)

(50u

gml)

(5ugm

l)

(05

ml)

(00

5ugm

l)

(00

1ugm

l)

(00

01ugm

l)

0

2000

4000

6000

3H

in

co

po

rati

on

(re

lati

ve p

roli

fera

tio

n)

OX40 antagonist


34


Treatment

0 20 40 600

50

100 Vehicle

Enbrel (8mgkg)



days

Perc

en

t su

rviv

al



35











36




Iso

typ

e

con

tro

l G

BR

83

0

Tem

ova

te

Donor 1-5

Isoty

pe co

ntrol

GBR83

0

Temova

te

0

50

100

150

200

250

Ep

iderm

al

thic

kn

ess (

m)

Donor 1 Donor 4

Iso

typ

e

con

tro

l G

BR

83

0

Tem

ova

te



37


Bispecific Antibody



Master-Cell Banking





38



39



Bispecific Antibody



Master-Cell Banking







40



CD3+ T cell

HER2+ Tumour Cell

41



cell line



42

0

20

40

60

80

100

No Ab

Ctrl BEAT

CD3 x Her2

Concentration (pM)

o

f s

pec

ific

kil

lin

g




43

44



45

Thank You



Leishmania major


OX40L acute



OX40-- acute




93

mCMV acute phase

OX40-- acute

Normal response


J Immunol 2007 Aug 15179(4)2195-202

mCMV chronic phase

OX40--

chronic


VSV OX40-- OX40L--

acute

Normal clearance




OX40-- acute



acute

Normal clearance





Immunity 1999 Dec11(6)699-708


Defective response



Mycobacterium avium

OX40L acute

Normal clearance





30

ProtozoaNematode

Virus

Bacteria


31






Atopic dermatitis

Psoriasis

Healthy control

Healthy control


Lupus nephritis

Ilves et al

Dolff et al

Souza et al

Patschan et al

SLE

IBD

CD3+ OX40+ CD4+ OX40+


Giacomelli et al

OX40 flow cytometry

Colon

Peripheral blood


32



OX

40

L

OX

40

T

C

R

OX

40

LOKT3

T-cell

OX

40

-Fc

OX

40

-Fc

OX

40

-Fc

OX

40

L

OX

40

L

OX

40

L

-4 -3 -2 -1 0 1 200

05

10


GBR 830

No Ab


OD

(450n

m)

10 10 1 01 001

0

50

100

Isotype control

GBR 830


Inh

ibit

ion

of

pro

life

rati

on

(

)

-8 -6 -4 -2 0 2 4-10

-5

0

5

10

15

20IgG1 control

GBR 830

GBR 830-IgG4hs


Sp

ecif

ic A

DC

C (

)

Readout Killing

NK cell

T-cell


33



effe

ctor

effe

ctor+

targ

et

Isoty

pe co

ntrol (

50ugm

L)

Efaliz

umab

(20u

gml)

Efaliz

umab

(2ugm

l)

Efaliz

umab

(00

2ugm

l)

(50u

gml)

(5ugm

l)

(05

ml)

(00

5ugm

l)

(00

1ugm

l)

(00

01ugm

l)

0

2000

4000

6000

3H

in

co

po

rati

on

(re

lati

ve p

roli

fera

tio

n)

OX40 antagonist


34


Treatment

0 20 40 600

50

100 Vehicle

Enbrel (8mgkg)



days

Perc

en

t su

rviv

al



35











36




Iso

typ

e

con

tro

l G

BR

83

0

Tem

ova

te

Donor 1-5

Isoty

pe co

ntrol

GBR83

0

Temova

te

0

50

100

150

200

250

Ep

iderm

al

thic

kn

ess (

m)

Donor 1 Donor 4

Iso

typ

e

con

tro

l G

BR

83

0

Tem

ova

te



37


Bispecific Antibody



Master-Cell Banking





38



39



Bispecific Antibody



Master-Cell Banking







40



CD3+ T cell

HER2+ Tumour Cell

41



cell line



42

0

20

40

60

80

100

No Ab

Ctrl BEAT

CD3 x Her2

Concentration (pM)

o

f s

pec

ific

kil

lin

g




43

44



45

Thank You


31






Atopic dermatitis

Psoriasis

Healthy control

Healthy control


Lupus nephritis

Ilves et al

Dolff et al

Souza et al

Patschan et al

SLE

IBD

CD3+ OX40+ CD4+ OX40+


Giacomelli et al

OX40 flow cytometry

Colon

Peripheral blood


32



OX

40

L

OX

40

T

C

R

OX

40

LOKT3

T-cell

OX

40

-Fc

OX

40

-Fc

OX

40

-Fc

OX

40

L

OX

40

L

OX

40

L

-4 -3 -2 -1 0 1 200

05

10


GBR 830

No Ab


OD

(450n

m)

10 10 1 01 001

0

50

100

Isotype control

GBR 830


Inh

ibit

ion

of

pro

life

rati

on

(

)

-8 -6 -4 -2 0 2 4-10

-5

0

5

10

15

20IgG1 control

GBR 830

GBR 830-IgG4hs


Sp

ecif

ic A

DC

C (

)

Readout Killing

NK cell

T-cell


33



effe

ctor

effe

ctor+

targ

et

Isoty

pe co

ntrol (

50ugm

L)

Efaliz

umab

(20u

gml)

Efaliz

umab

(2ugm

l)

Efaliz

umab

(00

2ugm

l)

(50u

gml)

(5ugm

l)

(05

ml)

(00

5ugm

l)

(00

1ugm

l)

(00

01ugm

l)

0

2000

4000

6000

3H

in

co

po

rati

on

(re

lati

ve p

roli

fera

tio

n)

OX40 antagonist


34


Treatment

0 20 40 600

50

100 Vehicle

Enbrel (8mgkg)



days

Perc

en

t su

rviv

al



35











36




Iso

typ

e

con

tro

l G

BR

83

0

Tem

ova

te

Donor 1-5

Isoty

pe co

ntrol

GBR83

0

Temova

te

0

50

100

150

200

250

Ep

iderm

al

thic

kn

ess (

m)

Donor 1 Donor 4

Iso

typ

e

con

tro

l G

BR

83

0

Tem

ova

te



37


Bispecific Antibody



Master-Cell Banking





38



39



Bispecific Antibody



Master-Cell Banking







40



CD3+ T cell

HER2+ Tumour Cell

41



cell line



42

0

20

40

60

80

100

No Ab

Ctrl BEAT

CD3 x Her2

Concentration (pM)

o

f s

pec

ific

kil

lin

g




43

44



45

Thank You


32



OX

40

L

OX

40

T

C

R

OX

40

LOKT3

T-cell

OX

40

-Fc

OX

40

-Fc

OX

40

-Fc

OX

40

L

OX

40

L

OX

40

L

-4 -3 -2 -1 0 1 200

05

10


GBR 830

No Ab


OD

(450n

m)

10 10 1 01 001

0

50

100

Isotype control

GBR 830


Inh

ibit

ion

of

pro

life

rati

on

(

)

-8 -6 -4 -2 0 2 4-10

-5

0

5

10

15

20IgG1 control

GBR 830

GBR 830-IgG4hs


Sp

ecif

ic A

DC

C (

)

Readout Killing

NK cell

T-cell


33



effe

ctor

effe

ctor+

targ

et

Isoty

pe co

ntrol (

50ugm

L)

Efaliz

umab

(20u

gml)

Efaliz

umab

(2ugm

l)

Efaliz

umab

(00

2ugm

l)

(50u

gml)

(5ugm

l)

(05

ml)

(00

5ugm

l)

(00

1ugm

l)

(00

01ugm

l)

0

2000

4000

6000

3H

in

co

po

rati

on

(re

lati

ve p

roli

fera

tio

n)

OX40 antagonist


34


Treatment

0 20 40 600

50

100 Vehicle

Enbrel (8mgkg)



days

Perc

en

t su

rviv

al



35











36




Iso

typ

e

con

tro

l G

BR

83

0

Tem

ova

te

Donor 1-5

Isoty

pe co

ntrol

GBR83

0

Temova

te

0

50

100

150

200

250

Ep

iderm

al

thic

kn

ess (

m)

Donor 1 Donor 4

Iso

typ

e

con

tro

l G

BR

83

0

Tem

ova

te



37


Bispecific Antibody



Master-Cell Banking





38



39



Bispecific Antibody



Master-Cell Banking







40



CD3+ T cell

HER2+ Tumour Cell

41



cell line



42

0

20

40

60

80

100

No Ab

Ctrl BEAT

CD3 x Her2

Concentration (pM)

o

f s

pec

ific

kil

lin

g




43

44



45

Thank You


33



effe

ctor

effe

ctor+

targ

et

Isoty

pe co

ntrol (

50ugm

L)

Efaliz

umab

(20u

gml)

Efaliz

umab

(2ugm

l)

Efaliz

umab

(00

2ugm

l)

(50u

gml)

(5ugm

l)

(05

ml)

(00

5ugm

l)

(00

1ugm

l)

(00

01ugm

l)

0

2000

4000

6000

3H

in

co

po

rati

on

(re

lati

ve p

roli

fera

tio

n)

OX40 antagonist


34


Treatment

0 20 40 600

50

100 Vehicle

Enbrel (8mgkg)



days

Perc

en

t su

rviv

al



35











36




Iso

typ

e

con

tro

l G

BR

83

0

Tem

ova

te

Donor 1-5

Isoty

pe co

ntrol

GBR83

0

Temova

te

0

50

100

150

200

250

Ep

iderm

al

thic

kn

ess (

m)

Donor 1 Donor 4

Iso

typ

e

con

tro

l G

BR

83

0

Tem

ova

te



37


Bispecific Antibody



Master-Cell Banking





38



39



Bispecific Antibody



Master-Cell Banking







40



CD3+ T cell

HER2+ Tumour Cell

41



cell line



42

0

20

40

60

80

100

No Ab

Ctrl BEAT

CD3 x Her2

Concentration (pM)

o

f s

pec

ific

kil

lin

g




43

44



45

Thank You


34


Treatment

0 20 40 600

50

100 Vehicle

Enbrel (8mgkg)



days

Perc

en

t su

rviv

al



35











36




Iso

typ

e

con

tro

l G

BR

83

0

Tem

ova

te

Donor 1-5

Isoty

pe co

ntrol

GBR83

0

Temova

te

0

50

100

150

200

250

Ep

iderm

al

thic

kn

ess (

m)

Donor 1 Donor 4

Iso

typ

e

con

tro

l G

BR

83

0

Tem

ova

te



37


Bispecific Antibody



Master-Cell Banking





38



39



Bispecific Antibody



Master-Cell Banking







40



CD3+ T cell

HER2+ Tumour Cell

41



cell line



42

0

20

40

60

80

100

No Ab

Ctrl BEAT

CD3 x Her2

Concentration (pM)

o

f s

pec

ific

kil

lin

g




43

44



45

Thank You


35











36




Iso

typ

e

con

tro

l G

BR

83

0

Tem

ova

te

Donor 1-5

Isoty

pe co

ntrol

GBR83

0

Temova

te

0

50

100

150

200

250

Ep

iderm

al

thic

kn

ess (

m)

Donor 1 Donor 4

Iso

typ

e

con

tro

l G

BR

83

0

Tem

ova

te



37


Bispecific Antibody



Master-Cell Banking





38



39



Bispecific Antibody



Master-Cell Banking







40



CD3+ T cell

HER2+ Tumour Cell

41



cell line



42

0

20

40

60

80

100

No Ab

Ctrl BEAT

CD3 x Her2

Concentration (pM)

o

f s

pec

ific

kil

lin

g




43

44



45

Thank You


36




Iso

typ

e

con

tro

l G

BR

83

0

Tem

ova

te

Donor 1-5

Isoty

pe co

ntrol

GBR83

0

Temova

te

0

50

100

150

200

250

Ep

iderm

al

thic

kn

ess (

m)

Donor 1 Donor 4

Iso

typ

e

con

tro

l G

BR

83

0

Tem

ova

te



37


Bispecific Antibody



Master-Cell Banking





38



39



Bispecific Antibody



Master-Cell Banking







40



CD3+ T cell

HER2+ Tumour Cell

41



cell line



42

0

20

40

60

80

100

No Ab

Ctrl BEAT

CD3 x Her2

Concentration (pM)

o

f s

pec

ific

kil

lin

g




43

44



45

Thank You



37


Bispecific Antibody



Master-Cell Banking





38



39



Bispecific Antibody



Master-Cell Banking







40



CD3+ T cell

HER2+ Tumour Cell

41



cell line



42

0

20

40

60

80

100

No Ab

Ctrl BEAT

CD3 x Her2

Concentration (pM)

o

f s

pec

ific

kil

lin

g




43

44



45

Thank You


Bispecific Antibody



Master-Cell Banking





38



39



Bispecific Antibody



Master-Cell Banking







40



CD3+ T cell

HER2+ Tumour Cell

41



cell line



42

0

20

40

60

80

100

No Ab

Ctrl BEAT

CD3 x Her2

Concentration (pM)

o

f s

pec

ific

kil

lin

g




43

44



45

Thank You


39



Bispecific Antibody



Master-Cell Banking







40



CD3+ T cell

HER2+ Tumour Cell

41



cell line



42

0

20

40

60

80

100

No Ab

Ctrl BEAT

CD3 x Her2

Concentration (pM)

o

f s

pec

ific

kil

lin

g




43

44



45

Thank You


Bispecific Antibody



Master-Cell Banking







40



CD3+ T cell

HER2+ Tumour Cell

41



cell line



42

0

20

40

60

80

100

No Ab

Ctrl BEAT

CD3 x Her2

Concentration (pM)

o

f s

pec

ific

kil

lin

g




43

44



45

Thank You



CD3+ T cell

HER2+ Tumour Cell

41



cell line



42

0

20

40

60

80

100

No Ab

Ctrl BEAT

CD3 x Her2

Concentration (pM)

o

f s

pec

ific

kil

lin

g




43

44



45

Thank You



cell line



42

0

20

40

60

80

100

No Ab

Ctrl BEAT

CD3 x Her2

Concentration (pM)

o

f s

pec

ific

kil

lin

g




43

44



45

Thank You




43

44



45

Thank You

44



45

Thank You

45

Thank You

Documents

Glenmark, an Indian Pharmaceutical Company in Switzerland ... IMPROVER NVC... · Glenmark, an Indian Pharmaceutical Company in Switzerland – Innovation with a touch of spice Sam