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CGEN-15001 A Novel B7-like protein controls inflammation in a translational RA assay and induces long term remission in autoimmune disease models

ACR, San Francisco, Nov 2015

Safe Harbor Statement

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CGEN-15001T – a novel B7-like Immune Checkpoint protein

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Adapted from J Clin Invest. 2010; 120(1):76-80

Mission: discovery of novel targets and develop first-in class biologics for key medical

needs, focusing on immunoncology and autoimmunity

Aim: discovery of novel members of the B7/CD28 family

CGEN-15001- an Fc fusion therapeutic candidate

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CGEN-15001 is a fusion protein: Fc + ECD of CGEN15001T

Inhibition of T Cell Activation by CGEN-15001 fusion proteinPolyclonal & Ag Specific Proliferation

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Polyclonal T cell activation Antigen specific T cell Activation

Naive DO11.10 CD4+ T cells

Irradiated APCs plus OVA323-339

Naive murine CD4+ T cells

anti-CD3/anti-CD28 coated beads + proteins

Robust inhibition of T cell proliferation following polyclonal or Ag specific activation

Demonstrated with various additional assays and readoutsMiller and Podojil, Northwestern Univ.

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DO11.10under Th1, Th17 or Th2 driving conditions

DO11.10 CD4+ T cells+

Irradiated APCs+

OVA323-339

# p<0.0001 vs. Ig control

IL-4IL-5

An

ti-i

nfl

am

ma

tory

#

IL-10

Th2

Th17

##

#

IL-10#

#

IL-17IFNγ

Pro

-in

fla

mm

ato

ry

#

Th1

#

Reduction of pro-inflammatory Th1 and Th17 responses

Enhancement of anti-inflammatory cytokines and Th2 responses

Similar ‘Th1/Th2 shift’ obtained with human cells and in recall responses obtained from mice with EAE following CGEN-15001 treatment

Immune balance restoration: Th1/Th17 to Th2 skew

Miller and Podojil, Northwestern Univ.

Enhancement of inducible regulatory T cells (iTregs) differentiation

7In house, Compugen, Tel Aviv

Immobilized

CGEN-15001 or

Control Ig

Soluble anti

CD28

Immobilize

d anti-CD3

CD4+ CD25-

CD25+FoxP3+ iTreg

CD25+FoxP3- T cell

iTreg induction

Activate

d T cell

±TGFβ and IL-2

4-5 days

FoxP3+

iTreg

+Naïve T cell

CGEN-15001 mediates immune modulation

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CGEN-15001 restores immune balance

• Inhibits T cell activation

• Skews the immune responses from Th1/Th17 to Th2

• Induces regulatory T cell (Treg) differentiation.

Inhibition of TNFa secretion in a translational assay mimicking T-cell:Macrophage interactions in RA synovium

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+15001

or Control Ig

CD4+

T cells

CD14+

monocytes

+TNFα, IL-6,

IL-15

+M-CSF

“Synovial-like”Cytokine stimulated T cells (TcK)

*10

0%

= 2

.3 ±

1.3

ng

Healthy donors

or

RA patients

McInnes, Glasgow Univ.

Autologous Tck:Mφco-cultures

ELISA (or Luminex)Monocyte-derived Mφ

CGEN-15001 pathway is

functional and responsive

in RA patients

Inhibition of RA-Related cytokines secretion in TcK:MF co-culture(normalized data, average of 4 donors)

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• Luminex results on additional cytokines: • Mild inhibition: IL-17, IL-13, IL-2R• No effect: IL-10, IL-15, IFNa, IL-7

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McInnes, Glasgow Univ.

(CCL3)

(CCL5)

Efficacy in Models of Autoimmune Diseases: Therapeutic Effect in Mouse Model of RA (CIA)

Inhibition of disease progression and reduced joint inflammation (similar to

positive controls, i.e. CTLA4-Ig and Enbrel)

Abolishment of recall response to type II collagen in LN cells

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Williams and McNamee, Oxford Univ.

DBA/1

Type II collagen/CFA Treatment at disease onset

i.p., 3x/wk for 10 days

Collagen Induced Arthritis (CIA)

Recall responses of LN cells

None Anti CD3 Type II

collagen

CP

M

Clinical score

Rx

Histological score

* p < 0.05, ** p < 0.01, *** p < 0.001 vs. IgG2a * p < 0.05, vs. PBS

Prevention of Type 1 Diabetes in NOD ModelSustained Long Term Efficacy

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Long standing reduction in disease

incidence following short term

administration to pre-diabetic

mice

Suggests tolerance induction

Prediabetic NOD(10 wks old)

i.p., 3x/wk for 2 wks

Blood glucose levels measured weekly, diabetes is defined as 2 consecutive measurements of >250 mg/dL.

Nonobese Diabetic Mice (NOD)

Rx

Miller and Podojil, Northwestern Univ.

n = 15 mice per group

Potential Re-establishment of Immune Tolerance in Models of Autoimmune Diseases and Transplantation

Rx (3x/wk x2 wks)

Long term reduction in disease score and inhibition of disease relapse

Inhibition of autoreactive T cell infiltration to the CNS and increase in spleen Treg number

Inhibition of epitope spreading (recall responses and DTH with spread epitopes peptides, not shown)

Th1/ Th17 to Th2 shift (in ex-vivo recall responses, not shown)

Teff and Tregs numbers

S p le e n (A c t iv a t io n M a rk e rs )

Tre

g c

ells

Eff

ect

CD

4+

T c

ells

MH

C II+

/B7+

M

MH

C II-

/B7+

M

MH

C II+

/B7+

DC

MH

C II-

/B7+

DC

0

1

2

3

4

5

6

9

1 2

1 5

1 8

C o n tro l Ig (1 0 0 u g /d o s e )

C G E N -1 5 0 0 1 (3 0 u g /d o s e )

C G E N -1 5 0 0 1 (1 0 0 u g /d o s e )

*

*

* *

*

Ce

ll N

um

be

r (x

10

6 c

ell

s)

Spleen

C N S (A c t iv a t io n M a rk e rs )

Tre

g c

ells

Eff

ect

CD

4+ T

cells

MH

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/B7+ M

MH

C II-

/B7+ M

MH

C II+

/B7+ D

C

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C II-

/B7+ D

C0 .0

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C g e n -1 5 0 0 1 (1 0 0 u g /d o s e )

* * * * * ** **

* *

* * *

Ce

ll N

um

be

r (

x1

04 c

ell

s)

Tregs Teffs

CNS

SJL

PLP 139-151 Treatment at onset of remission

i.p., 3x/wk for 2 wks

Active R-EAE (relapsing EAE)

Tregs Teffs

CGEN-15001 induced long-term remission is mediated by Tregs

Transient neutralization of Tregs leads to transient abolishment of the long term remission

induced by CGEN-15001

The effect of CGEN-15001 depends on newly generated Ag specific Tregs rather than

existing Tregs14

SJL

PLP 139-151 Treatment with CGEN-15001 or Isotype control i.p., 3x/wk for 2 wks from onset of remissionA. Concomitant administration of anti-CD25 (7D4) or Control AbB. Late administration of anti-CD25 (2wks after the last treatment with

CGEN-15001

Miller and Podojil, Northwestern Univ.

CGEN-15001 - A potential candidate for treatment of RA and other autoimmune disease

A novel inhibitory immune checkpoint pathway

Translational data:

Inhibition of RA-related cytokines and chemokines secretion in ‘synovial-like’ co-cultures with RA patients’ cells

Efficacious in multiple models of autoimmune diseases

CIA (RA), R-EAE (MS), T1D (in NOD), psoriasis (not shown)

Durable in vivo effects upon short term treatment in EAE and T1D

Unique mechanism of action

Restoration of immune balance: Th1/Th17 to Th2 skew

Potential induction of Treg-dependent peripheral immune tolerance

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Acknowledgments

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Compugen

Eyal Neria

Zurit Levine

Galit Rotman

Amir Toporik

Ilan Vaknin

Anat Oren

Elisheva Yonish-Rouach

Rami Khosravi

Zohar Tiran

Inbal Barbiro

Oxford Univ.

Richard Williams

Kay McNamee

Stephen D. Miller

Joseph R. Podojil

Northwestern Univ.

Iain B. McInnes

Mariola Kurowska-Stolarska

Ashley Gilmour

Clare Tange

Donna McIntyre

Glasgow Univ.

Thank you