selective modulation of fc receptors for improved therapy of … · may 5, 2015. presentation...

Selective Modulation of Fc Receptors for Improved Therapy of Orphan Autoimmune Diseases: Lessons from IVIg

Anthony M. Manning, PhD

VP Research

May 5, 2015

Presentation Outline

• Unmet Needs in Autoimmune Disease

• Key Role for FcgR System in Pathogenesis & Learnings from IVIg

• Rational Design of SIFs

• Pre-clinical Profile of SIF3

• Next Steps in Development

2

Over 80 distinct diseases, 50 million Americans affected, $100B+ annual economic burden

NIH Autoimmune Diseases Coordinating Committee 2013; AARDA Report 2011

Rh

eum

ato

id A

rth

riti

s

Psoriasis Asthma IBD Multiple Sclerosis

Ankylosing Spondylitis Dermatomyositis Mysthemia GravisLupus APS

6.5 million

PATIENTS

2million

PATIENTS

13million

PATIENTS

1million

PATIENTS

370thousandPATIENTS

600thousandPATIENTS

150thousandPATIENTS

130thousandPATIENTS

70thousandPATIENTS

40thousandPATIENTS

Psoriasis Rheumatoid Arthritis Asthma IBD Multiple Sclerosis

There is an Immunologic Basis for Many Diseases

3

NMO: Neuromyelitis optica; CIDP: Chronic inflammatory demyelinating polyneuropathy; ANCA: ANCA associated vasculitis; MG: Myasthenia gravis; APS: Antiphospholipid syndrome; GBS: Guillain-Barre Syndrome; ITP: Idiopathic thrombocytopenic purpura; Sources: Orphanet, Medscape, Triangle Insights’ analysis, Health Advances’ analysis

500,0001,500,0002,500,0003,500,0004,500,0005,500,0006,500,0007,500,000 Psoriasis

Rheumatoid arthritis

Psoriatic arthritisUlcerative colitis

Crohn’sAnkylosing spondylitis

U.S. diagnosed prevalence of 16 autoimmune indications

0

20,000

40,000

60,000

80,000

100,000

120,000

140,000

160,000Systemic lupus erythematosus

APS

MGANCA

CIDP

NMO

U.S

. dia

gno

sed

pre

vale

nce

GBS

ITP

Pemphigus/pemphigoid

Dermatomyositis/polymyositis

Autoimmune Indications … A Tale of Two Cities

4

• Recent innovation driving improved patient care and significant market value

• Robust pipelines but mostly incremental advances

• Unmet need exists but biological basis unclear


500,0001,500,0002,500,0003,500,0004,500,0005,500,0006,500,0007,500,000 Psoriasis




US diagnosed prevalence of 16 autoimmune indications

0

20,000

40,000

60,000

80,000

100,000

120,000

140,000


APS

MGANCA

CIDP

NMO

US

dia

gno

sed

pre

vale

nce

GBS

ITP




5

• More than 70 distinct diseases

• Lack of recent innovation to satisfy high unmet medical needs

• Few agents in development

• Recent innovation driving improved patient care and significant market value

• Robust pipelines but mostly incremental advances

• Unmet need exists but biological basis unclear


500,0001,500,0002,500,0003,500,0004,500,0005,500,0006,500,0007,500,000 Psoriasis




US diagnosed prevalence of 16 autoimmune indications

0

20,000

40,000

60,000

80,000

100,000

120,000

140,000


APS

MGANCA

CIDP

NMO

US

dia

gno

sed

pre

vale

nce

GBS

ITP




6

IVIg BenlystaNplate & Promacta

$0

$100

$200

$300

$400

$500

$600

$700

$800

$900

$1,000

$1,100

2011

2012

2013

2014

2015

2016

2017

2018

2019

2020

WW

re

ven

ue

($

M)

Anti-BAFF antibody

Chronic maintenance of SLE

Approved 2011

Incremental improvement

2013 WW sales $228M

$0

$100

$200

$300

$400

$500

$600

$700

$800

$900

$1,000

$1,100

2008

2009

2010

2011

2012

2013

2014

2015

2016

2017

2018

2019

2020

WW

re

ven

ue

($

M)

Nplate Promacta

TPO agonists

Third-line agents in ITP

Not disease-modifying

Approved 2008

Combined 2013 WW sales $718M

IgG fraction from pooled plasma of ~10K donors

Approved therapy for PID and 5 inflammatory diseases

Used in >50 other indications

2013 WW sales $6.2Bn

$0.0

$2.0

$4.0

$6.0

$8.0

$10.0

2009

2010

2011

2012

2013

2014

2015

2016

2017

2018

WW

sal

es

($B

n)

Innovation in a Low-prevalence Autoimmune Disease Creates Substantial Value

7

Auto-antibodies Mediate Disease and Are Not Targeted by Current Therapeutics

8

Auto-antibodies and immune complexes mediate tissue damage and dysfunction in

autoimmune and inflammatory disease

Therapeutic strategies that indirectly target auto-antibody production have

been only partially successful

Strategies that directly target auto-antibodies and immune complexes have

proven valuable in challenging clinical settings, but have limited utility in chronic

or maintenance settings

Anti-DNA ANCA Anti-Rho

Central Role for Fcg Receptors in Autoantibody-mediated Diseases

9

IVIG Activity is Replicated by the Fc Domain Alone

10

A c u te IT P S tu d ie s

L o g D o s e [µ m o le s /k g ]

% P

late

let

Re

co

ve

ry

-0 .5 0 .0 0 .5 1 .0

0

2 0

4 0

6 0

8 0

1 0 0

IV Ig

F c

HillSlope

EC50

IVIg

0.6449

1.091

Fc

0.5144

0.8932

• Fc domain provides equivalent efficacy to IVIG in the mouse ITP model • Fc materials derived from IVIg or recombinant Fc are comparable

Murine anti-CD41-induced Acute Thrombocytopenia Model

Fc Fragment is Efficacious in Humans

11

Fc fragment efficacy is comparable to IVIG or corticosteroids in ITP patients*

0 1 2 3 4 5 6

Day

400

300

200

100

0Pla

tele

t co

un

t x 1

09/L

Platelet recovery after IVIG Fc Fragment

• 0.75g/kg Fc

Platelet recovery after IVIG or methylprednisolone (MP)

Pediatric ITP patients Balkan et al 20092g/kg IVIG

30 mg/kg MP

But Fc fragment halflife is short

Fc Fragments (43 hrs)

IVIG (19 days)

Pediatric ITP patients Debre et al 1993

Adult patients or volunteersJaneway et al 1968

Efficacy was also shown with the Fc fragment in Kawasaki disease Hsu et al 1993

*

25-50 kDa Fc fragments are rapidly eliminated via renal excretion

Proprietary IPDA algorithms

Momenta bio-characterization toolkit

Application of Momenta Patient Bio-characterization Toolkit

Kawasaki’s disease study FcR biology index

Subj 1

Subj 2

Subj 3

Subj 4

Subj 5

Subj 6

-1 0 2 3 51 4

Normal range

= Pre-IVIg = Post-IVIg

IVIg Treatment Suppresses FcR biology

12

IgG Receptors Play a Key Role in Disease and Therapy

A family of receptors binding the Fc portion of IgGs

Key mediators of auto-antibody and immune complex functions

Genetic variants associated with autoimmune diseases

IgG Receptors

FcγRI FcγRIIA FcγRIIB FcγRIIC FcγRIIIA FcγRIIIB FcRn

α

β2mα-GPI

α2γαα

ITIMαα2γ

Activation Activation Activation ActivationInhibition ActivationRecycling TransportAg uptake…

13

FcgR Modulation Profiles that Might Offer Benefit in Autoimmune Disease

14

Broad FcgRModulation

Specific FcgRModulation

Spectra of Fcg-Receptor Family Modulation

IVIg

FcgR Ratio Modulation

Specific Abs

IVIg-like (Broad Modulation)

Target FcgR Ratio Specific FcgR

Supported primarily by mouse data & human cell assays & emerging

competitor agents

Supported primarily by IVIg MOA Theoretical based on a compilation of mouse data & human

expression data

SIF3: Powerful Anti-inflammatory Agent Fully Harnessing IVIg Mechanism of Action

FcgR binding

> 100x increased affinity than IVIg

mM

nM

IVIg

SIF

15

• Homogeneous recombinant Fc-derived product

• IVIg-like specificity for FcgRs

• Unique molecular design enhances avidity and potency to modulate FcgRbiology

• Potent antagonist of autoantibody-mediated diseases

FcM=

µg/ml µg/ml

RF

U

(Ma

x-M

in)

Co

ntr

ol

FcM IC

IVIg

0

2 0

4 0

6 0

8 0

1 0 0

Establishing the SAR for Polymeric IgG Fc’sLarge Polymers of Fc Activate FcgR’s

Calcium Release in Monocytes

FcgR Signaling in MonocytesFc Multimer

p /t S y k

Fo

ld C

ha

ng

e

FcM

FcM

-LM

W

FcM

-F1

FcM

-F2

FcM

-F3

FcM

-F4

0

2 0

4 0

6 0

F c M

F c M -L M W

F c M -F 1

F c M -F 2

F c M -F 3

F c M -F 4

SDS-PAGE of Fc Multimer Fractions Monocyte Activation by Fc Multimer Fractions

Polymeric IgG Fc Results in Cellular ActivationSize Matters

A Library of Multimeric-Fc Structures

18

Diversity of Molecular Structures…. …..Assessed for Fc Receptor Modulation

Including unique mutations that regulate ordered subunit association

Structure-Activity Relationship of Polymeric Fc’s Size Matters

F c g R IIIa V 1 5 8

IC5

0 (m

M)

CH

mo

no

mer

no

rmal tr

imer ,

CK

H

inver t

ed

tr i

mer

pen

tam

er

X

pen

tam

er

Y

0 .0 0 0 1

0 .0 0 1

0 .0 1

0 .1

1

FcgRIIIA Receptor Binding Affinity

Increased apparent affinity driven by increased avidity

p /t S y k

m g /m l

Fo

ld C

ha

ng

e

0.0

0.0

05

0.0

2

0.0

5

0.1

4

0.4

1

1.2

3

3.7

0

11.1

33.3

100

0

1 0

2 0

3 0

4 0

5 0

Ig G 1

IV Ig

F c 1

F c 2

F c 3 Y

F c 3 L

F c 5 X

F c 5 Y

Structure-Activity Relationship of Polymeric Fc’s Size Matters

Ca Release in Primary Human Monocytes

FcgR Signaling in Primary Human Monocytes

Multimers Display Enhanced Avidity to FcgReceptors

Multimerization increased low affinity FcgR binding through avidity

21

F c g R IIb

IC5

0 (

mg

/mL

)

Fc1

Fc2

Fc3

1 .01 0 -3

1 .01 0 -2

1 .01 0 -1

1 .01 0 0

F c g R I

IC5

0 (

mg

/mL

)F

c1

Fc2

Fc3

0

5 .01 0 -6

1 .01 0 -5

1 .51 0 -5

F c g R IIIa

IC5

0 (

mg

/mL

)

Fc1

Fc2

Fc3

1 .01 0 -5

1 .01 0 -4

1 .01 0 -3

1 .01 0 -2

1 .01 0 -1

1 .01 0 0

F c g R IIa

IC5

0 (

mg

/mL

)

Fc1

Fc2

Fc3

1 .01 0 -6

1 .01 0 -5

1 .01 0 -4

1 .01 0 -3

1 .01 0 -2

1 .01 0 -1

1 .01 0 0

Notes: Logarithmic y-axis for FcγRIIIa, IIa, and IIb. Lower IC50 = Higher relative affinity.

170x650x

80x

1980x

10x

210x

1x

0.5x

Minimal changes for FcgRI

P re -T re a tm e n t C o n d it io n

RF

U

(Ma

x-M

in)

Med

ium

100u

g/m

L S

IF 3

Med

ium

100u

g/m

L S

IF 3

Med

ium

100u

g/m

L S

IF 3

0

5

1 0

1 5

2 0

2 5

4 4 0 mg /m L IC

4 4 mg /m L IC

V e h ic le

SIF3 is a Potent Antagonist of Immune-Complex-mediated FcgR Activation

Ca Release in Primary Human Monocytes

FcgR Signaling in Primary Human Monocytes

Phagocytosis in Monocytes

IL -8

u g /m l

pg

/ml

0 .0 0 0 1 0 .0 1 0 .1 1 1 0 1 0 0

0

1 0 0 0 0

2 0 0 0 0

3 0 0 0 0

IV Ig

S IF 3

p b Ig G 1

IgG

1 a

lon

e

In h ib it io n o f P h a g o c y to s is in P r im a r y M o n o c y te s

n g /m l

% i

nh

ibit

ion

1 0 -2 1 0 0 1 0 2 1 0 4 1 0 6

0

2 0

4 0

6 0

8 0

1 0 0

1 2 0

IV Ig

S IF 3

F c -B lo c k

SIF3 Inhibits Multiple Cellular Functions of FcgReceptors

Cytokine Production in Monocytes

Ca Release in Neutrophils Cytokine Production in PBMCs

• Fc-trimer displayed 100-fold higher potency than IVIg

24

A c u te IT P a C D 4 1 -0 0 7

IV Ig v s . F c 2 v s . F c 3

lo g IV Ig /F c D o s e [g /k g ]

Pla

tele

t P

ro

tec

tio

n [

%]

-3 -2 -1 0

0

2 0

4 0

6 0

8 0

1 0 0

1 2 0

a C D 4 1 (3 .5 u g ) + IV Ig

a C D 4 1 (3 .5 u g ) + F c 2

a C D 4 1 (3 .5 u g ) + F c 3

Murine anti-CD41-induced Acute Thrombocytopenia Model

A c u te IT P a C D 4 1 -0 0 7

IV Ig v s . F c 2 v s . F c 3

lo g IV Ig /F c D o s e [g /k g ]

Pla

tele

t P

ro

tec

tio

n [

%]

-3 -2 -1 0

0

2 0

4 0

6 0

8 0

1 0 0

1 2 0

a C D 4 1 (3 .5 u g ) + IV Ig

a C D 4 1 (3 .5 u g ) + F c 2

a C D 4 1 (3 .5 u g ) + F c 3

IC50 IVIg = 338 mg/kgIC50 rFc dimer = 93 mg/kgIC50 rF trimer = 30 mg/kg

SIF3 Displays Enhanced Potency in an Acute ITP Mouse Model When Compared to IVIg

P l a t e l e t L e v e l s D a y 5

I so

t yp

e (

1. 5

ug

) +

Sa

l in

e

CD

41

( 1. 5

ug

) +

Sa

l in

e

CD

41

( 1. 5

ug

) +

IV

I g a

t 1

g/ K

g

CD

41

( 1. 5

ug

) +

M- 1

13

at

0. 0

04

g/ K

g

CD

41

( 1. 5

ug

) +

M- 1

13

at

0. 0

2 g

/ Kg

CD

41

( 1. 5

ug

) +

M- 1

13

at

0. 1

g/ K

g

0

3 0 0

6 0 0

9 0 0n o r m a l r a n g e

Pla

te

le

t 1

09

/L

IVIg Fc3Controls

Da

y 0

Da

y 1

Da

y 2

Da

y 3

Da

y 4

Da

y 5

Da

y 6

Da

y 7

Da

y 8

Da

y 9

Da

y 1

0

0

2

4

6

8

1 0

1 2

M - 1 1 3 , 0 . 1 g / k g

M - 1 1 2 , 0 . 1 g / k g

I V I g , 0 . 1 g / k g

P B S c o n t r o l

I V I g , 1 g / k g

Av

er

ag

e C

lin

ica

l S

co

re

SIF3 Displays Enhanced Efficacy and Potency in K/BxNand ITP Mouse Models When Compared to IVIg

K/BxN Serum Transfer Arthritis ModelMurine anti-CD41 Antibody-induced Chronic Thrombocytopenia Model

• Fc2 and Fc3 at 0.1 g/kg showed similar levels of protection to IVIg at 1 g/kg indicating that Fc2 and Fc3 were more potent than IVIg

• Chronic ITP model suggest ~50 times potency increase for Fc3 over IVIg

M112= Fc2M113= Fc3

Inhibition of complement deposition in the paws

SIF3, 0.05 g/kgIVIg 1 g/kgVehicle

IVIg 1 g/kg

SIF3, 0.05 g/kg

Vehicle

SIF3 Suppresses Collagen-Antibody-Induced Arthritis

Greater potency and efficacy than IVIg

27

28 Day Multi-Dose Safety Assessment in Mice

Day 0

PrebleedPK & ADA

Day -5

Day 7

Cytokines Day 3

PK, ADA & Tissue Paramters

Assessment parameters :• PK assay: day -5, 6, 13, 20 & day 27• ADA assays: day -5, 6, 13, 20 & day 27• Cytokines: day -5, 3, 10, 13, 17 & 27• Complement deposition in tissues-IHC Day 13 & 27• Complement assay with Plasma• PAF assay: day 13 & 27• Blood cell count, Vet Scan: Day 13 & 27• Toxicity/Clinical chemistry: Day 13 & 27• Tissue assessment

Day 21

Study Design

Day 14

Dosing with SIF3 @ 0.1g/kg and 0.01g/kg iv

PK & ADA Day 6

CytokinesDay 10

Collection of tissues PK & ADA

Day 13

CytokinesDay 17

PK & ADA Day 20 Day 27

Urine collection for baseline readout

Day 13

SIF3 was well-tolerated and no remarkable findings were observed

SIF3 Has Appropriate Properties for Manufacturing

• Product is homogenous >98 % trimer by CE-SDS

• Titers greater than 3 g/l in early cell line development

28

0

20

40

60

80

100

120

0 4 7 14

% b

y SE

C

Time (days)

Stability at 45C :SEC profiling of main species @ 45C

SIF3

IgG1

0

20

40

60

80

100

T=0 T=3h T=6h T=24h

Are

a-%

Stability at pH 3:SIF SEC profiling

Hexamer

Penatmer

Trimer

Dimer

Monomer

0

20

40

60

80

100

120

T= 0 T= 3h T= 6h T= 24h

Are

a-%

Stability at pH 3: IgG1 SEC profiling

Aggregate-1

Aggregate-2

Aggregate-3

IgG1

Next Steps in Development

• SIF3 is in pre-clinical development

• Anticipate initiation of clinical trials in 2H 2016

• Potential in multiple autoimmune diseases with autoantibody-mediate pathology and activated FcgR system

• Potential as a personalized therapy

29

selective modulation of fc receptors for improved therapy of … · may 5, 2015. presentation...

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