www.delenex.com

www.delenex.com
®
PENTRA Body
The
Platform: Rapid Discovery of Highly Potent
Femtomolar to Low Picomolar Antibody Fragments
Nicole Dreier, Douglas Phillips, Japar Shamshiev, Miriam Steinwand, Verena Strassberger, Stefanie Grabulovski, Anna Bianca Howald, Marco Landi,
Andrea Marti, Camilla Winnewisser, Julia Molitor, Titus Kretzschmar
Delenex: The PENTRA®Body Company
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Key Advantages of PENTRA®Bodies
Clinical stage therapeutic antibody company, founded in 2009
Focused on dermatology and oncology
Proprietary PENTRA®Body platform: highly attractive and
validated
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Highly stable
Highly potent (≤ 600 femtomolar (IL-1b)) without lengthy
affinity maturation
Small, excellent tissue penetration
GMP production at low cost of goods
Clinical study in dermatology established proof-of-concept of
topical administration
Safe and well tolerated
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PENTRA®Bodies are:
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Antibody fragments of about 25 kDa
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Building blocks are single-chain format, can be assembled into
other formats (e.g. IgG, Fab, bispecific)
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Pipeline
The
®
PENTRA Body
PENTRA®Bodies
Standard mAb
Other Antibody
Fragments/Scaffolds
Molecular weight
25 kDa
150 kDa
< 20 kDa
Plasma half-life
~1 day
~3 weeks
~minutes to hours
high
very low
likely high
fM to low pM
pM
nM
no
no
required
Tissue penetration
Potency
Affinity maturation
Platform
CDRs typically obtained by rabbit immunization;
may also be obtained from library display, IgGs etc.
Frameworks
Product
(Target)
Indication
DLX105
(TNFα)
Psoriasis (intradermal)
Psoriasis (topical)
Hidradenitis Suppurativa
Ophthalmology
DLX2751
(TNFα)
Lead
Preclinic
1b/2a
2
Single B cell sorting
completed
Human spleen derived VLlinker-VH antibody library (> 107)
completed
Highly potent, highly stable
25 kDa humanized
PENTRA®Bodies without
affinity maturation
ESBA105
Antigen-independent
selection in yeast for
highly stable VL / VH
combinations
Psoriasis (topical)
Hidradenitis Suppurativa
DLX2323/2681 Acne
(IL-1β)
Acute gout
DLX3003
(IL-17A)
Psoriasis
DLX1008
(VEGF-A)
Kaposi Sarcoma, Rosacea
Oncology (Glioblastoma)
Ophthalmology
Protein-based
immunization
Laser
Lymph node
cell isolation
Rapid screening for
neutralizing antibodies
Masterset of novel, very stable
VL-linker-VH human antibody
frameworks
HRP
Cells
Anti-rabbit-IgG
target
RNA isolation
RT-PCR
Sequencing of VH & VL
ESBA1008/RTH258
ELISA screening
Signal
Rabbit-IgG
target
VEGF: High Potency DLX1008 for Glioblastoma
Two clinical studies performed:
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Intradermal injection of anti-TNFα DLX105
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Local inhibition of TNFα gave a clinical
response in mild-to-moderate plaque psoriasis
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DLX105 has an excellent safety profile
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Systemic exposure with anti-TNFα antibodies is
obviously not required for a therapeutic effect in
psoriasis
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Study results offer an option for topical
therapies based on antibodies
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DLX1008 binds human and mouse VEGF-A with 27 and 22 pM
monovalent affinities (KD), resp.
DLX1008 (=ESBA1008, RTH258) is in phase II clinical trials in
wet AMD (Novartis)
High unmet medical need in glioblastoma
Anti-VEGF IgG Avastin® (bevacizumab, Roche) approved for
glioblastoma in US, but not in Europe
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Topical administration of anti-TNFα DLX105
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mRNA levels of key pro-inflammatory biomarkers were significantly decreased compared to
placebo (e.g. TNFα, p< 0.001)
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Clinical readout (PASI score) did not show a significant difference from placebo
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The translation of these biological effects into a meaningful clinical response is dependent on
the concentration of locally-deposited DLX105 and most likely requires improved penetration
into deeper dermis
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Longer treatment periods (as is the case for etanercept), increasing drug concentration in
the dermis and/or a more potent follow-on anti-TNFα PENTRA®Body might result in clinical
efficacy
Binding of DLX1008 to human VEGF:
Quartz Crystal Microbalance
Coated DLX1008, VEGF165 as analyte
DLX1008 expected to be superior to bevacizumab due to good
tissue distribution and high affinity combined with its small size
Fast to market approach identified, development started
IL-17A: High Potency DLX3003 for Psoriasis
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In vitro neutralization of IL-17A
IC50 of ≤ 5.1 pM determined by highly sensitive
cell-based assay (patent application filed)
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600
IL - 6 , p g /m l
TNFα: Clinical Proof-of-Concept with DLX105
No affinity maturation required, 6 months from
start to hit
Topical treatment of mild-to-moderate psoriasis
Use of anti-IL-17A PENTRA®Bodies beyond
systemic anti-IL-17A IgG antibodies
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400
D LX3003
c o n tro l s c F v
200
0
0 .1
1
10
100
1000
10000
100000
A n tib o d y , p M
The single-chain anti-TNFα antibody DLX105 induces a clinical response in psoriasis patients when administered intradermally
presented at the 41st Annual ADF meeting in Cologne, Germany, 2014, March 13
Patrick Brunner1, Athanasios Tsianakas2, Claudia Berger3, Georg Stingl1, Thomas Luger2, Thomas Jung3
1 Dept. of Dermatology, DIAID, Med. Univ. Vienna, Austria, 2 Dept. of Dermatology, Univ. Münster, Germany, 3 Delenex Therapeutics AG, Zürich, Switzerland
IL-1β: ≤ 600 Femtomolar (IC50) DLX2681
PENTRA®Body 1
29 pM
Outlook:
2
0
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PENTRA®Bodies can be
formatted into 52 kDa bispecific
format without any loss of potency
Simultaneous binding to both
targets
Parallel neutralization of two
targets offers benefits in a variety
of diseases
Prokaryotic expression suitable
100
1000
10000
100000
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Reformatting
Tendency towards smaller
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antibody fragments in ADC field
PENTRA®Body properties are
ideal for ADCs:
− small
− tissue penetrating
− high affinity
PENTRA®Bodies allow sitespecific toxin conjugation
a
m
u
100
100
100
22°C
100
100
100
37°C
100
99.6
99.3
IgG and Fab formats
possible without any
loss of potency
25 kDa PENTRA®Bodies
• Have a unique combination of:
− high stability
− femtomolar to low picomolar potency
− excellent tissue penetration
− rapid discovery
− solid patent protection
• Are suitable building blocks for other formats
e.g. bispecific constructs, ADCs
• Are clinically validated in phase II studies
tr
n
o
4°C
C
day 14
o
n
D LX2681
ki
D LX2323
n
day 7
b
/k
,
ls
1
g
0
cF
m
v,
g
/k
1
g
0
m
g
/k
g
g
g
1
0
1
m
m
g
g
/k
/k
g
g
/k
m
.1
A n tib o d y , p M
g
10000
/k
1000
m
100
0
10
g
1
g
0 .1
/k
0 .0 1
g
0
0
a
day 0
Summary
As Building Blocks
Antibody Drug Conjugates
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10
A n tib o d y , p M
Bispecific PENTRA®Bodies
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1
30 pM
®
PENTRA Bodies
% monomer content (by HPLC analysis) after storage
temperature
200000
0 .1
PENTRA®Body
500
a
D LX105
Section 1 Title
400
0
PEN TR A Body 2
1000
800
1
®
400000
Ila r is
m
®
PEN TR A Body 1
D LX2323
1500
g
600000
D LX2681
2000
1
800000
1200
C
soluble TNFa
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In vitro activity
m
IC50
In vitro neutralization of soluble TNFa
In vivo efficacy: inhibition
of human IL-1β induced
IL-6 production in mice
.1
Antibody
62 times more potent than canakinumab
(Ilaris®, Novartis)
Highly stable antibody fragment
Potently inhibits hIL-1b induced inflammation
in mice
Potential indications for topical / systemic
administration
− Acne vulgaris
− Flaring gouty arthritis
− others, such as hidradenitis suppurativa
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Substantially improved potency compared to DLX105
(factor of 10)
Differences in inhibition of transmembrane TNFα
Leads for confirmatory clinical studies in psoriasis
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IL - 6 , p g /m l
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IC50 of ≤ 600 fM: best-in-class
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PENTRA®Bodies
C e ll s u r v iv a l
TNFα: Next Generation
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IL -6 , p g /m l
Topical administration of the single-chain anti-TNFα antibody DLX105 suppresses TNFα and Th17 cytokines in psoriatic skin
presented at the 44th Annual ESDR Meeting in Copenhagen, Denmark, 2014, September 11
Athanasios Tsianakas1, Patrick Brunner2, Kamran Ghoreschi3, Claudia Berger4, Karin Loser1, Martin Röcken3, Georg Stingl2, Thomas Luger1, Thomas Jung4
1 Dept. of Dermatology, Univ. Münster, Germany, 2 Dept. of Dermatology, DIAID, Med. Univ. Vienna, Austria, 3 Dept. of Dermatology, Univ. Tübingen, Germany, 4 Delenex
Therapeutics AG, Zürich, Switzerland
Delenex Therapeutics AG
Wagistrasse 27
8952 Schlieren
Zurich
Switzerland
www.delenex.com
[email protected]