Download MCLA-128 - Jefferies

20 May 2015
The Immuno-Oncology Company
BATTLING CANCER WITH BISPECIFIC ANTIBODIES
NON-CONFIDENTIAL
COMPANY SNAPSHOT
Bispecific Antibody Leader
Blue-chip Investors
Raised $ 60 M in VC funding
Lead therapeutic: start of clinical trials in
Feb 2015.
Pipeline: 5 Immuno-Oncology therapeutics
in clinical trials by Q2/18
Bispecific antibody-based, technology
platform – partnership with ONO
pharmaceutical
HQ Utrecht, The Netherlands - 38
employees
20 May 2015
NON-CONFIDENTIAL
Adapted from Bispecifics Antibody Therapeutics Market (2014 Roots Analysis)
CURRENT PIPELINE – Q2 2015
Drug
Targets
disease
MCLA128
HER2 x HER3
Solid
tumors
MCLA117
CD3 x
CLEC12A
AML
MCLA122
EGFR x HER3
Solid
tumors
MCLA134
PD1 x TIM-3
Solid
tumors
MCLAxxx
iMOD x
iMOD.
Solid
tumors
MCLAyyy
Cancer stem
cell targets
Solid
tumors
Not disclosed
AID
AID = autoimmune disease
20 May 2015
NON-CONFIDENTIAL
Discovery
IND enabling
Phase I/II
for outlicensing
Partnered ONO PHARMACEUTICAL
PIPELINE Q1 2015 → Q2 2018
mezz proceeds
Drug
Targets
disease
MCLA-128
HER2 x HER3
Solid
tumors
MCLA-117
CD3 x CLEC12A
AML
2015
IPO proceeds
2016
2017
2018
Single agent
Combination
Single agent
Combination
MCLA-122
EGFR x HER3
Solid
tumors
MCLA-134
PD1/PD-L1 x YYY
Solid
tumors
MCLA-xxx
iMOD x iMOD
Solid
tumors
MCLA-yyy
cancer stem cell
target combinations
Solid
tumors
Discovery
Tox batch Mfg
20 May 2015
for outlicensing
Clinical batch Mfg & non clinical safety studies
Phase I/II
NON-CONFIDENTIAL
optional
STRATEGY – WHY BISPECIFIC ANTIBODIES
Novel mode
of action
Large target
combination
space
Improved
specificity/
targeting
Functional
screening
Attractive
pharmacoeconomics
Developability
20 May 2015
NON-CONFIDENTIAL
MISSION & OVERALL STRATEGY
Develop differentiating therapeutics to
cure cancer patients
Bispecific antibodies (Biclonics®) that kill tumor cells and
recruit the immune system for prolonged survival
revive T cells to kill
kill the tumor (stem) cell
CD28
CTLA-4
OX40
Tumor
cell
PD-1
TIM-3
GITR
CD137
T cell
LAG-3
CD27
20 May 2015
NON-CONFIDENTIAL
T cell
Tumor
cell
BTLA
HVEM
ADCC-enhanced
activate/recruite T cells to kill
VISTA
?
?
Fc-silenced
DISCOVERY AND DEVELOPMENT OF BICLONICS®
Human antibodies
phage display
MeMo® transgenic mouse
Common light chain (cLC)
Biclonics®: full length IgG
human bispecific
antibodies
Fc region engineering
CH3: > 99% pure Biclonics®
CH2: Fc-silencing
Low fucosylation: enhanced
ADCC
CHO
cLC
Stability like IgG
cLC
Fcsilencing
ADCCenhanced
normal pK in mice/cyno
behaviour like IgG in
antibody stress tests
20 May 2015
Manufacturability
stability: > 60 passages
yield: > 1 g/L
scalability: 2000 L
formulation: standard
Dependable IgG format
with true platform
characteristics
NON-CONFIDENTIAL
®
PRODUCT STRATEGY - ONCOLOGY
Receptor
tyrosine kinases
20 May 2015
Cancer stem
cells
Target
combinations of
growth factor
receptors for
ADCC-enhanced
tumor cell killing
Kill the cells that
cause relapse and
are resistent to
most therapies
Activate T cells
irrespecive of
specificity to
selectively kill
tumor cells
Modulate immune
checkpoint
molecules to
unleash tumorspecific T cells
NON-CONFIDENTIAL
T cell
retargeting
Immunemodulation
BICLONICS® DISCOVERY PROCESS - OVERVIEW
Steps in Biclonics® discovery:
• generation of high quality panels of common light chain human monoclonal antibodies
• functional screening of > 1000 Biclonics® for lead panel identification
• final lead selection after multiple in vitro assays and in vivo animal models
Generation of large panels of
human antibodies
1.
Target pair for
immunization and
phage selections
9-12
months
2.
Production of ~1000
different Biclonics®
for functional screens
3.
Functional screening in
cell-based assays
Lead Biclonics®
selection
1
June 2015
6/1/2015
CONFIDENTIAL
9
DISCOVERY STRATEGY – FUNCTIONAL SCREENING
Functional screening of thousands of different Biclonics® supports the
identification of differentiating therapeutics
Cell growth
Functional screen of 750 Biclonics® for inhibition/
stimulation of cancer cell growth (EGFR x HER3)
20
inhibition
% normalized cell growth
stimulation
0
-20
-40
BxPC3 ligand independent assay
Best in class anti-cancer
drug
BxPC3
EGF + HRG dependent assay
-60
Biclonics® with superior
inhibition of cell growth
20 May 2015
NON-CONFIDENTIAL
without heregulin
heregulin
20 May 2015
MCLA-128 (HER2 x HER3)
KEY PRECLINICAL DATA
NON-CONFIDENTIAL
MCLA-128 FOR TARGETED THERAPY IN SOLID TUMORS
MCLA-128: HER2 x HER3 Biclonics® for HER2+ solid tumors
High unmet medical need
designed to overcome inherent and acquired
resistance to HER2-targeted therapies
Attractive clinical development
phase I/II design is focused on biomarker defined
patient populations and yields early safety and
efficacy data
Unique mode of action
dual action: blocks HER2/HER3-driven growth and
escape; enhanced ADCC for immune effector cell
engagement
First-in-Human Study:
Tumor
cell
20 May 2015
NK cell
NON-CONFIDENTIAL
first patient dosed on
February 03, 2015
MCLA-128: UNIQUE MODE OF ACTION
In contrast to trastuzumab + pertuzumab and HER3 monoclonal antibodies,
MCLA-128 completely inhibits heregulin-driven cancer cell growth.
N87 HER2-amplified cell line stimulated with heregulin
SKBR-3 cell line stimulated with heregulin
4
3
2
0
20 May 2015
NON-CONFIDENTIAL
Akt
thr308
1
Akt
ser473
LJM 716
heregulin
T+P
MCLA-128
Erk1/2
AMG-888
MM 121
Fold change in phosphorylation
% heregulin driven growth
MCLA-128: UNIQUE MODE OF ACTION
In contrast to trastuzumab + pertuzumab, MCLA-128 inhibits the growth of cell
lines resistant to HER-2 targeted therapies
• JIMT-1 is an aggressive breast cancer line resistant to lapatinib, trastuzumab +
pertuzumab and T-DM1).
MCLA-128: > 80% reduction in tumor size
MCLA-128: > 50% survival after 60 days
100
vehicle
Vehicle
MCLA-128
MCLA-128
TTrastuzumab
+P
+ Pertuzumab
100
Percent survival
Tumor volume (mm3)
1000
50
vehicle
MCLA-128
T+P
0
0
20
40
60 Days
mice dosed 4qw @ 2.5 mg/kg
20 May 2015
NON-CONFIDENTIAL
0
20
40
60
Days
20 May 2015
MCLA-117 (CD3 x CLEC12A)
KEY FACTS – DATA - DIFFERENTIATION
NON-CONFIDENTIAL
BICLONIC® ENGAGERS FOR IMMUNOTHERAPY
MCLA-117: CD3 x CLEC12A Biclonics® for AML
High unmet medical need
little change in standard treatment in 40 years; no
cure available; increasing patient population
Rapid iv administration and
superior to antibody fragments; eligible for Orphan
IgG-like dosing schedules;
Drug Designation ( EU/US); high chance of breakattractive clinical development through designation (FDA);
Unique mode of action
T cell
retargeting T cells via novel AML target with
restricted tissue expression; kills tumor (stem) cells
AML blast
CD3
First-in-Human Study:
Q1, 2016
Tumor (stem) cell
20 May 2015
NON-CONFIDENTIAL
CLEC12A – RESTRICTED TISSUE EXPRESSION
a myeloid differentiation antigen only expressed on certain blood cells
present on 95% of newly diagnosed and relapsed AML
selective expression on AML tumor stem cells
• not present on normal hematopoetic stem cells
• not present on red blood cell and platelet precursor cells
CLEC12A expression on AML stem cells
% CLEC12A
CD34+CD38- cells
100
%
7
5
5
0
2
5
0
AML BM
20 May 2015
NON-CONFIDENTIAL
Normal BM
rB
M
MCLA-117 EFFICIENTLY MEDIATES AML TUMOR CELL
KILLING
Recruits and activates T cells to lyse CLEC12A -expressing autologous
AML tumor cells.
MCLA-117 induces antigen-specific T cell activation and proliferation
TotalTTcells
cells
Total
CD4
T cells CD8 TCD8
CD4
T cells
cells T cells
Ctrl
IgG
Ctrl IgG
T cell
CD3
CD3 IgG
IgG
AML blast
CD3xTT
TT x CD3
ctrl
Biclonics®
Ctrl Biclonics®
counts
MCLA-117
MCLA-117
®
Biclonics
Biclonics®
CFSE
20 May 2015
NON-CONFIDENTIAL
CSFE
MCLA-117 EFFICACY IN PRIMARY AML MATERIALS (I)
Specific and efficient lysis of a patient’s AML tumor cells by low
numbers of T cells present in primary samples
T cell population expands as a result of MCLA-117
Day 10
ctrl Biclonics®
Day 0
Day 10
MCLA-117
81%
93%
1%
16%
CD34
CD34
5%
CD3
CD3
T cell expansion
CLEC12A
Isotype
Tumor cell killing
CLEC12A expression
on AML blasts
20 May 2015
NON-CONFIDENTIAL
96%
20 May 2015
Biclonics® for immunomodulation
Overall survival
UNCOVERING THE RIGHT TARGET COMBINATIONS FOR
DIFFERENTIATING THERAPEUTICS
control
standard of care
immunotherapy
Immunotherapy combinations
‘Lifting the curve’
Time
NON-CONFIDENTIAL
Improving survival of cancer
patients
Breakthrough
of the Year
2013
BICLONICS® IN CANCER IMMUNOTHERAPY
What target combination will trump?
• increase frequency and/or duration of responses in patients
• manageable toxicity (autoimmunity)
Merus - three different approaches based on Biclonics®:
• block two checkpoint inhibitory pathways
• block a checkpoint inhibitory pathway and provide a costimulatory signal
• target an overexpressed signalling receptor & an immunomodulatory pathway
OX40
PD-1
CD28
TIM-3
GITR
CTLA-4
T cell
CD137
LAG-3
CD27
BTLA
HVEM
agonistic
20 May 2015
PD-1 x OX-40
VISTA
?
NON-CONFIDENTIAL
?
blocking
PD-1 x TIM-3
BISPECIFIC - MONOVALENCY
dual targeting of 2 antigens on the same cell leads to improved target
selectivity over normal tissues
• that express only one target or express low levels of targets (same cell)
• over-expression of a tumor target may direct bispecific to the tumor environment
favorable toxicity profile compared to a combination of antibodies ??
combination
A
B
overexpression
tumor
+
+
normal
+
-
Tumor
cell
20 May 2015
Normal
cell
NON-CONFIDENTIAL
A
B
tumor
+++
+
normal
+
+
Tumor
cell
Normal
cell
targeting
A
B
tumor
+++
+
normal
+
+
Tumor
cell
T cell
A UNIQUE MODULAR DISCOVERY STRATEGY
Antibody panels are combined in the Biclonics® format for functional screening
• antibody panels for 6 IMOD targets generated and 4 more planned for 2015
• screen in functional assays for differentiating activities of Biclonics ongoing with
current focus on PD-1 and PD-L1 centric approaches (one arm = PD-1 or PD-L1)
Functional screens
PD-1
centric
Reporter cell line
PD-L1
centric
Exhausted T cells
(HIV, Miha)
TIM-3
AAA
EGFR
ZZ
BBB
CCC
ZZ
ZZ
TILS
Lead
20 May 2015
NON-CONFIDENTIAL
iMOD targets
RTK targets
HIGHLIGHTS
Unique technology suite
• human bispecific antibodies based on the proven IgG format
• high throughput functional screening for the identification of
bispecific antibodies with unique functional properties
• manufactured using industry standard processes
• predictable in vivo behavior associated with IgG format
A pipeline of differentiating therapeutics in oncology
• modes of action that can not be achieved with conventional
therapeutic antibodies
• recruitment of the immune system for unprecedented tumor
cell killing
An extremely attractive investment opportunity
20 May 2015
NON-CONFIDENTIAL
T cell
AML blast
Tumor
cell
20 May 2015
Thank you for your attention
TON LOGTENBERG
CEO
NON-CONFIDENTIAL