Engineering Multi-functionality into Antibodies Engineering Multi-functionality into Antibodies

17 Pages·2014·2.87 MB·English

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Barry Springer, Ph.D.
V.P. and Head of Biologics Technology, Strategy, and External Partnering
Janssen R&D, Pharmaceutical Companies of J&J
Texas FreshAIR Immuno-Oncology October 23, 2014
Biotechnology Center of Excellence
Janssen Research & Development, LLC
Antibody Engineering Technologies are Transforming
the Immuno-Onc Strategy and Approach
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Multi-specifics in the Pharma Pipeline
Bispecific or Bifunctional Abs in the Clinic
Names of Biologics Company Targets Platform Indication Current Phase
Stelara Janssen IL12 & IL23,  IgG1 Psoriasis Approved
bifunctional
bindingto p40 
subunit
Non‐hodgkins
20‐2b 20‐2b INFalphaR/CD20 dock & lock Lymphoma Ph II
Rheumatoid 
ABT122 Abbott TNF/IL‐17 DVD‐Ab arthritis Ph1
ABT981 Abbott IL‐1 alpha & beta DVD‐Ab Osteo Arthritis Ph 1
Hodgkins  Ph 1/2a (AFM13‐
AFM13 Affimed CD30/CD16a TandAb Lymphoma 101)
Blinatumomab (MT103) Amgen (Micromet) CD3/CD19 BiTE ALL, NHL Ph 2
MT‐110 Amgen (Micromet) CD3/EpCAM BiTE Solid tumors Ph 1
Gastrointestinal 
MT‐111 (MEDI‐565)  Amgen (Micromet) CEA/CD3 BiTE cancer Ph 1
MT‐112 (BAY2010112) Bayer/Amgen PMSA/CD3 BiTE Prostate Cancer Ph 1 CTA submitted
Advanced Solid 
CVX241 CovX (Pfizer) VEGF/Ang2 mAb peptide fusion Tumors Ph 1
ETI‐204 (Anthim) ElusysTherapeutics RCB CR1 x Anthrax Chemically fused antibodies Anthrax infection Ph 2
Catumaxomab (Removab) Fresenius/Trion CD3/EpCam mouse/rat Malignant Ascities Approved
Ertumaxomab Fresenius/Trion HER2/CD3 mouse/rat Breast cancer Ph 2
FBTA05, With Donor 
Lymphocyte Infusion Fresenius/Trion CD20/CD3 mouse/rat? B‐cell lymphoma Ph 2
GSK‐2434735 GSK IL‐13/IL4 domain antibody (Domantis) Asthma Completed Ph 1
Rheumatoid 
COVA‐322 Covance TNF/IL-17 IgG1 ‐Fynomer arthritis Ph1
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In the beginning….STELARA® (ustekinumab)
First in Class Human Anti-IL-12/23 p40 Monoclonal Antibody
• Approved for moderate to severe plaque psoriasis in 72 countries
• Offers unprecedented convenience with only 4 doses per year
• Winner of Prix Galien award US and International for best biotech
product
Kauffman CL, et al. J Invest Dermatol 2004;123:1037-1044.
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Multiple Platforms Producing Multi-Specifics
at Janssen
• Bispecific Abs – Genmab DuoBody platform
Bivalent,
bispecific
• Ab-alternative scaffold hybrids
– Centyrins
– Fynomers
• Alternative Scaffolds
• Peptides
Tetravalent, Tetravalent, Tetravalent,
bispecific trispecific tetraspecific
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Genmab DuoBody Bispecific Antibody Technology
IgG1 Bivalent,
T cell mediated LYSIS
monospecific
T cell
IgG1 Bivalent,
bispecific
**
Mild
reduction
and
**
re-oxidation
**
Cancer
cell
Labrijn et al. 2013 Efficient generation of stable bispecific IgG1
by controlled Fab-arm exchange PNAS 110:5145-5150
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Oncogenic Drivers in Lung Adenocarcinoma
• Primary EGFR mutations (ex19del,
KRAS
PI3K L858R) occur in ~17% non-Asian
and ~50% Asian patients with lung
adenocarcinoma
EGFR
Other
• Patients treated 1st line with EGFR
tyrosine kinase inhibitor (TKI) 
erlotinib, gefitinib, afatinib
• 70% response rate but all acquire
MET
resistance and relapse
INSR
PDGFR
ALK
EPHA/B
ROS
HER2
BRAF
VEGFR
Modified from Blakely and Bivona, Cancer Discovery; 2012,
2:872-875; with adaptations from R. Herbst
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JNJ-372 Binds EGFR and cMet With High Affinity
and Inhibits Ligand Binding to Each Receptor
HGF
EGFR cMet
 JNJ-372 binds EGFR-ECD with  JNJ-372 binds cMet-ECD with
K = 1.4 nM, 25x tighter K = 39 pM, 820x tighter
D D
binding than EGF ligand binding than HGF ligand
 JNJ-372 inhibits binding of EGF  JNJ-372 inhibits binding of
to EGFR-ECD HGF to cMet-ECD
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Bispecific Shows Increase in Potency Compared to
Combination of Monospecific mAbs
H292 Cells
EGFR wt; MET wt
4000
EGFR monospecific
n=3
3000
l
a
n
g
i
s cMet monospecific
2000

K
R
E
p
1000
Combination
+
0
IC = 35 nM
-2 -1 0 1 2 3 50
Treatment Conc. log[nM]
Bispecific JNJ-372
55-fold increase in potency
IC = 0.64 nM
50
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JNJ-372 in EGFR Mutant/ MET Amp PDX Model
Compared to Erlotinib + MetMab
LU858
EGFR: L858R; MET amp 
2500
2000 Vehicle
3
m Erlotinib+Metmab
m Erlotinib
Metmab
/ 

e
m 1500 Afatinib
u
l
o
v

r
u
o
m 1000
u
t

n
a
e
M
500
JNJ-372
Dosing phase
0
0 10 20 30 40 50
Days
Patient Explant Model
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