Embracing Complexity: Understanding IVIg to Rationally ...€¦ · 5/5/2014 · Presentation...
Transcript of Embracing Complexity: Understanding IVIg to Rationally ...€¦ · 5/5/2014 · Presentation...
Embracing Complexity: Understanding IVIg to Rationally Design Novel Therapeutics
Anthony M. Manning, PhD
VP Research
May 5, 2014
Presentation Outline
• The Momenta approach to product development
• Application to intravenous immunoglobulin (IVIg) and autoimmune diseases
• New products that may deliver enhanced benefit to IVIg
• Sialylation of IVIg
• Sialylation of recombinant IgG’s
• Recombinant products
2
Momenta Embraces ComplexityThree Critical Components to Deliver Medicines
Understanding the
nonlinear chemical
and biosynthetic
reactions that drive
production
Control of Manufacturing
*
*
High resolution physicochemical
analytics platform to fully
characterize any product
Thorough Structural
Characterization
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Thorough Biological
Characterization
High resolution biology
analytics platform to fully
characterize any product
in non- and clinical
settings
• Generic Lovenox®• Generic Copaxone®
(under FDA review)
Biosimilars & Potentially Interchangeable Biologics
• M402 oncology Phase 1
Novel DrugsANDA Generics
Momenta has Extended this Approach to IVIgand Autoimmune Diseases
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Complex Mixture Drugs
Intravenous Immunoglobulins
Complex Diseases
RA, Lupus, Psoriasis, etc
• IgG fraction derived from pooled plasma of ~10K donors
• Approved therapy for PID and 5 inflammatory diseases; used in ~100 other indications
• Poorly characterized mixture and MOA debated
• Dysregulation of complex immune system underlies >100 distinct diseases
• ~50M Americans affected
• Significant unmet needs despite recent advances
IVIg Is An Important….but Poorly Understood Anti-inflammatory Therapeutic
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Widely Used as an Anti-inflammatory Poorly Understood MOA
Thorough Physicochemical Characterization Defines IVIg Composition
6
7
Thorough Physicochemical Characterization Defines IVIg Composition
100
200
300
400
500
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>500
Number of distinct data readouts in characterization of IVIg lots
EU Pharmacopeia Momenta
IgG isotypesIgG1 Fc glycoformsIgG2 Fc glycoformsIgG3 Fc glycoformsIgG4 Fc glycoformsIgG2 disulfidesIgG4 mixed antibodiesIgG allotypesIgG Fc glycoform asymmetryConformational aggregatesAnti-idiotypic Ab complexesGlycationIgG1 Fab glycoformsIgG2 Fab glycoformsIgG3 Fab glycoformsIgG4 Fab glycoformsDeamidationOxidationGlycationDistribution of antigen specificityNon-IgG proteins……..
Dat
a R
ead
ou
ts
Thorough Biocharacterization Defines IVIgMechanism of Action
Genetic
Glycan
Protein and Cellular
Metabolic
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Patients
Deep understanding of biological
mechanisms of action of existing
therapies & unmet medical needs
New Drugs
Combination of orthogonal analytics and informatics to deconstruct disease networks and complex mechanisms
Model Systems
CAIA
EAE
KBxN
ITP
Thorough Characterization Reveals New Products that May Deliver Improved Patient Benefits
• Sialylation of the Fc region of IVIg• Exploits natural mechanism of modulating IgG function
• Potential for lower dose, higher potency Ig products (e.g. SC delivery)
• Improved Ig products, targeted to existing or new inflammatory disorders
• Sialylation of the Fc region of biologic therapeutics• Enhanced anti-inflammatory activity of any recombinant biologic
• Novel Recombinant Products• Exploit major mechanisms of action of IVIg
• Homogeneous recombinant products with improved patient safety
• Potential to integrate anti-inflammatory properties of controlled sialylation
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Alterations in the Sialylation of IgG are Associated with Autoimmune Disease and Disease Activity
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Normal range
RA patients
Parekh et al., 1988
RA and JIA Patients have less Sialylation (and its Precursor Galactosylation) in their IgG
Vehicle
Fc
IVIG
sialylated Fc
K/BxN arthritis model
Anthony, R. & Ravetch, J et al., 2008US8470318US7846744
US 20130273040
sFc and Fc dose: 0.035 g/kgIVIG dose: 1 g/kg
Sialylation of the Fc region of IgG mediates enhanced anti-inflammatory activity
SCIENCE VOL 320 18 APRIL 2008
We Optimized the Enzymatic Process for Site-Specific Sialylation
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+B4GalT1
ST6Gal10
20406080
100
Re
l. a
bu
nd
ance
(%
)
IgG1
IgG2
IgG3/4
020406080
100
Re
l. a
bu
nd
ance
(%
)
IgG1
IgG2
IgG3/4
0
10
20
30
40
Re
l. a
bu
nd
ance
(%
)
IgG1
IgG2
IgG3/4
> 80% Pure S2- IVIg
> 80% Pure S1-IVIg
IVIg Drug Substance
IVIg
S1-I
VIg
S2-I
VIg
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Avoiding Undesirable Modifications Introduced in Original Process
ST6 enzyme produced from certain sources can introduce other chemical modifications into the product. These modifications could impact biological
functions, which could confound results if not controlled.
Modifications Introduced During Sialylation Process
ST6 Enzyme Source
Original Optimized
Carboxymethyl lysine 5% ND
Carboxymethyl arginine 10% ND
Methylglyoxal arginine 20% 2%
Imidazolidine 8% ND
Pentosidine Yes ND
Sialylated IVIg Suppresses Arthritis in the K/BxNSerum Transfer Model of Arthritis
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Serum Arthritis31.01.2014 - 07.02.2014
0 1 2 3 4 5 6 7 8 9 100.0
2.5
5.0
7.5
10.0
12.5+1g/kg Mha-048674
+0.3g/kg Mha-048674
PBS
[days]
clinic
al score
treatment
IVIg 1 g/Kg
IVIg 0.3 g/Kg
PBS
Sialylated IVIg (S-IVIg) reveals better efficacy than IVIg. IVIg loses activity at 0.3 g/Kg whilst sialylated IVIg shows good activity at 0.3 g/Kg
Serum Arthritis31.01.2014 - 07.02.201414.02.2014 - 24.02.2014
0 1 2 3 4 5 6 7 8 9 100.0
2.5
5.0
7.5
10.0 +0.3g/kg JCl-044545
+0.1g/kg JCl-044545
+1g/kg Mha-048674treatment
PBS
[days]
clinic
al score
IVIg 1 g/Kg
S-IVIg 0.1 g/Kg
PBS
S-IVIg 0.3 g/Kg
In collaboration F. Nimmerjahn et al
Sialylation Is Required for Efficacy of IVIg in a Mouse Model of Immune Thrombocytopenia
0
5
10
15
20
25
30
35
G0
F
G1
F
G2
F
G0
G1 G2
G0
F+B
Glc
NA
c
G1
F+B
Glc
NA
c
G2
F+B
Glc
NA
c
A1
F1,3
A1
F1,6
A2
F
G1
F+N
eu
Ac
A1
1,3
A1
1,6 A2
A1
F+B
Glc
NA
c 1
,3
A1
F+B
Glc
NA
c 1
,6
A2
F+B
Glc
NA
c
G1
F+N
eu
Ac+
BG
lc…Re
lati
ve a
bu
nd
ance
(%
)
IgG1
IgG2
IgG3/4
IVIg
IgG1
IgG2/3
IgG4
0
5
10
15
20
25
30
35
40
G0
F
G1
F
G2
F
G0
G1 G2
G0
F+B
Glc
NA
c
G1
F+B
Glc
NA
c
G2
F+B
Glc
NA
c
A1
F1,3
A1
F1,6
A2
F
G1
F+N
eu
Ac
A1
1,3
A1
1,6 A2
A1
F+B
Glc
NA
c 1
,3
A1
F+B
Glc
NA
c 1
,6
A2
F+B
Glc
NA
c
G1
F+N
eu
Ac+
BG
lcN
Ac
Re
lati
ve a
bu
nd
ance
(%
)
IgG1
IgG2
IgG3/4
Desialylated IVIG
IgG1
IgG2/3
IgG4
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Murine anti-CD41 Antibody-induced Thrombocytopenia Model
Increased Sialylation of IVIg Accelerates Platelet Recovery in a Murine Model of ITP
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0102030405060708090
G0
F
G1
F
G2
F
G0
G1 G2
G0
F+B
Glc
NA
c
G1
F+B
Glc
NA
c
G2
F+B
Glc
NA
c
A1F
1,3
A1F
1,6
A2F
G1
F+N
euA
c
A1F
-Lac
NA
c
A1
1,3
A1
1,6 A2
A1F
+BG
lcN
Ac
1,3
A1F
+BG
lcN
Ac
1,6
A2F
+BG
lcN
Ac
G1
F+N
euA
c+B
Glc
NA
c
Re
l. a
bu
nd
ance
(%
)
IgG1
IgG2
IgG3/4
05
10152025303540
G0
F
G1
F
G2
F
G0
G1 G2
G0
F+B
Glc
NA
c
G1
F+B
Glc
NA
c
G2
F+B
Glc
NA
c
A1F
1,3
A1F
1,6
A2F
G1
F+N
euA
c
A1F
-Lac
NA
c
A1
1,3
A1
1,6 A2
A1F
+BG
lcN
Ac
1,3
A1F
+BG
lcN
Ac
1,6
A2F
+BG
lcN
Ac
G1
F+N
euA
c+B
Glc
NA
c
Re
l. a
bu
nd
ance
(%
)
IgG1
IgG2
IgG3/4
IVIg
sIVIg
Murine anti-CD41 Antibody-induced Thrombocytopenia Model
Sialylated IVIg Suppresses Skin Blistering in a Murine Model of Pemphigus
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IVIg dose titration
EBA Score(14.02.2014 - 27.02.2014)
3 4 5 6 7 8 9 10 11 120
5
10
15
20
+0.3g/kg 048674
+0.6g/kg 048674
+1g/kg 048674
+Saline
days
aff
ecte
d b
ody a
rea [
%]
PBS
IVIg 1.0 g/Kg
IVIg 0.6 g/Kg
IVIg 0.3 g/Kg
PBS
IVIg 0.3 g/Kg
S-IVIg 0.3 g/Kg
3 4 5 6 7 8 9 10 11 12
0
5
10
15
20
days
aff
ecte
dbody
are
a[%
]
In collaboration F. Nimmerjahn et al
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0
5
10
15
20 ****
day 1
2
aff
ecte
d b
od
y a
rea
[%
]
PBS
S-IVIg 0.3 g/Kg
S-IVIg 0.3 g/KgIVIg 0.3 g/Kg
Sialylated IVIg Suppresses Skin Blistering in a Murine Model of Pemphigus
In collaboration with F. Nimmerjahn et al
* p> 0.05*** p> 0.01
Thorough Characterization Reveals New Products that May Deliver Improved Patient Benefits
• Sialylation of the Fc region of IVIg• Exploits natural mechanism of modulating IgG function
• Potential for lower dose, higher potency Ig products (e.g. SC delivery)
• Improved Ig products, targeted to existing or new inflammatory disorders
• Sialylation of the Fc region of biologic therapeutics• Enhanced anti-inflammatory activity of any recombinant biologic
• Novel Recombinant Products• Exploit major mechanisms of action of IVIg
• Homogeneous recombinant products with improved patient safety
• Potential to integrate anti-inflammatory properties of controlled sialylation
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Sialylation of Recombinant Fc or an Anti-Cytokine mAb Enhances Suppression of Murine Arthritis
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Mea
n A
rth
riti
s Sc
ore Normal mice
Vehicle/DiseasePrednisoneIgG1 at 7.5 mg/KgSialylated IgG1 at 7.5 mg/Kg
MNT-KBN-004 Total Delta
0
20
40
60
IL-4, ic
sFc, 0.1 g/kg
Fc, 0.1 g/kg
PBS
IVIg, 1.2gm/kg
Ave
rag
e D
elt
a C
ali
pe
r M
ea
su
rem
en
t
Murine Anti-Collagen Antibody-Induced ArthritisMurine K/BxN Serum Transfer Arthritis
• Anti-inflammatory effect of Fc sialylation can be transferred to recombinant products
Thorough Characterization Reveals New Products that May Deliver Improved Patient Benefits
• Sialylation of the Fc region of IVIg• Exploits natural mechanism of modulating IgG function
• Potential for lower dose, higher potency Ig products (e.g. SC delivery)
• Improved Ig products, targeted to existing or new inflammatory disorders
• Sialylation of the Fc region of biologic therapeutics• Enhanced anti-inflammatory activity of any recombinant biologic
• Novel Recombinant Products• Exploit major mechanisms of action of IVIg
• Homogeneous recombinant products with improved patient safety
• Potential to integrate anti-inflammatory properties of controlled sialylation
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Thorough Characterization of Kawasaki Disease (KD) Patients Reveals IVIg Treatment Signature
Kawasaki’s Disease Inflammation of the coronary
arteries pre-disposing to aneurysms (ballooning) and
stenosis (narrowing) of the arteries.
>700 analytes per sample
19,467 data points
In collaboration with J.C. Burns et al
Genome
Glycome
Proteome
Metabolome
Advanced Data Analytics Reveals IVIg Treatment Signatures
• Acute Phase
• FC-gamma Receptor Signaling
• Granulocyte Chemotaxis
• Defense Response to Bacterium
• Positive Regulation of NF-kappaB Activity
• ………..
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Pri
nci
pal
Co
mp
on
ent
An
alys
isC
om
po
ne
nt
2
Component 1
Cluster 1 Cluster 2
Cluster 1: Active disease + developing aneurysms
Cluster 2: Resolved disease + IVIG response
Identified analytesand their associated pathways which are major differentiators
of cluster1 vs 2
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 M-113Controls
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
Novel Recombinant Products Leverage IVIg MOA Resulting in Significantly Enhanced Potency
K/BxN Serum Transfer Arthritis Model
• >1,000-fold enhancement of molecular mechanism• >50-fold enhancement of in vivo efficacy versus IVIg
Murine anti-CD41 Antibody-induced Thrombocytopenia Model
Acknowledgements
• Jeffrey Ravetch, Rockerfeller University
• Falk Nimmerjahn, University of Erlangen-Nuremberg
• Robert Anthony, Harvard
• Jane Burns, UCSD
• Frank Austen, Harvard
• Momenta Team
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