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The Immuno-Oncology CompanyBATTLING CANCER WITH BISPECIFIC ANTIBODIES
NON-CONFIDENTIAL
20 May 2015
20 May 2015
COMPANY SNAPSHOT
Blue-chip Investors
Raised $ 60 M in VC funding
Lead therapeutic: start of clinical trials in Feb 2015.
Bispecific antibody-based, technology platform – partnership with ONO pharmaceutical
Pipeline: 5 Immuno-Oncology therapeutics in clinical trials by Q2/18
HQ Utrecht, The Netherlands - 38 employees
NON-CONFIDENTIAL
Adapted from Bispecifics Antibody Therapeutics Market (2014 Roots Analysis)
Bispecific Antibody Leader
20 May 2015 NON-CONFIDENTIAL
CURRENT PIPELINE – Q2 2015
Drug Targets disease Discovery IND enabling Phase I/II
MCLA-128
HER2 x HER3Solid
tumors
MCLA-117
CD3 x CLEC12A
AML
MCLA-122
EGFR x HER3Solid
tumors
MCLA-134
PD1 x TIM-3Solid
tumors
MCLA-xxx
iMOD x iMOD.
Solidtumors
MCLA-yyy
Cancer stem cell targets
Solid tumors
for outlicensing
Not disclosed AID Partnered ONO PHARMACEUTICAL
AID = autoimmune disease
20 May 2015 NON-CONFIDENTIAL
PIPELINE Q1 2015 → Q2 2018
Drug Targets disease 2015 2016 2017 2018
MCLA-128 HER2 x HER3Solid
tumors
MCLA-117 CD3 x CLEC12A AML
MCLA-122 EGFR x HER3Solid
tumors
MCLA-134 PD1/PD-L1 x YYYSolid
tumors
MCLA-xxx iMOD x iMODSolid
tumors
MCLA-yyycancer stem cell
target combinationsSolid
tumors
for outlicensing
Single agent
Combination
Single agent
Combination
Phase I/II
Clinical batch Mfg & non clinical safety studiesDiscovery
Tox batch Mfg
optional
mezz proceeds IPO proceeds
20 May 2015 NON-CONFIDENTIAL
STRATEGY – WHY BISPECIFIC ANTIBODIES
Large target combination
space
Improved specificity/targeting
Novel mode of action
Attractive pharmaco-economics
Functional screening
Developability
20 May 2015
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
NON-CONFIDENTIAL
revive T cells to kill
T cell
CTLA-4
PD-1
TIM-3
LAG-3
BTLA
VISTA
CD28
OX40
GITR
CD137
CD27
HVEM
? ?
T cell Tumor cell
activate/recruite T cells to kill
Fc-silenced
kill the tumor (stem) cell
Tumor cell
ADCC-enhanced
20 May 2015 NON-CONFIDENTIAL
DISCOVERY AND DEVELOPMENT OF BICLONICS®
phage displayMeMo® transgenic mouseCommon light chain (cLC)
Human antibodies
stability: > 60 passagesyield: > 1 g/Lscalability: 2000 Lformulation: standard
ManufacturabilityStability like IgG
normal pK in mice/cynobehaviour like IgG in antibody stress tests
Biclonics®: full length IgG human bispecific
antibodies
CHO
CH3: > 99% pure Biclonics®
Fc region engineering ®
Dependable IgG format with true platform
characteristics
CH2: Fc-silencing
Fc-silencing
ADCC-enhanced
Low fucosylation: enhanced ADCC
cLC cLC
20 May 2015 NON-CONFIDENTIAL
PRODUCT STRATEGY - ONCOLOGY
Cancer stem cells
Kill the cells that cause relapse and
are resistent to most therapies
Target combinations of
growth factor receptors for
ADCC-enhanced tumor cell killing
Receptor tyrosine kinases
Activate T cells irrespecive of specificity to
selectively kill tumor cells
T cellretargeting
Modulate immune checkpoint
molecules to unleash tumor-specific T cells
Immune-modulation
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
CONFIDENTIAL
BICLONICS® DISCOVERY PROCESS - OVERVIEW
6/1/2015 9
Target pair for immunization and phage selections
Functional screening in cell-based assays
Production of ~1000 different Biclonics®
Lead Biclonics®
selection
Generation of large panels of human antibodies
9-12 months
for functional screens
1.
2.
3.
1 June 2015 9
Functional screening of thousands of different Biclonics® supports the identification of differentiating therapeutics
20 May 2015 NON-CONFIDENTIAL
DISCOVERY STRATEGY – FUNCTIONAL SCREENING
-60
-40
-20
0
20
BxPC3 ligand independent assay
BxPC3 EGF + HRG dependent assay
% n
orm
alized
cell g
row
th
Cell growth
stimulation
inhibition
Biclonics® with superior inhibition of cell growth
Functional screen of 750 Biclonics® for inhibition/ stimulation of cancer cell growth (EGFR x HER3)
Best in class anti-cancer drug
without heregulin
heregulin
MCLA-128 (HER2 x HER3)KEY PRECLINICAL DATA
20 May 2015
NON-CONFIDENTIAL
20 May 2015 NON-CONFIDENTIAL
MCLA-128 FOR TARGETED THERAPY IN SOLID TUMORS
MCLA-128: HER2 x HER3 Biclonics® for HER2+ solid tumors
First-in-Human Study:
first patient dosed on February 03, 2015
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
Tumor cell
NK cell
In contrast to trastuzumab + pertuzumab and HER3 monoclonal antibodies, MCLA-128 completely inhibits heregulin-driven cancer cell growth.
20 May 2015 NON-CONFIDENTIAL
MCLA-128: UNIQUE MODE OF ACTION
% heregulin -driven growth
0
1
2
3
4
Erk1
/2
Akt
se
r47
3
Akt
th
r30
8
Fold
ch
ange
in p
ho
sph
ory
lati
on
SKBR-3 cell line stimulated with heregulin
heregulinT + PMCLA-128
N87 HER2-amplified cell line stimulated with heregulin
LJM 716
MM 121
AMG-888
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).
20 May 2015
MCLA-128: UNIQUE MODE OF ACTION
0 20 40 600
50
100
Days
Percen
t su
rviv
al
NON-CONFIDENTIAL
MCLA-128: > 80% reduction in tumor size
mice dosed 4qw @ 2.5 mg/kg
0 20 40 60
100
1000
Vehicle
MCLA-128
Trastuzumab
+ Pertuzumab
Days
Tu
mo
r v
olu
me (
mm
3)
MCLA-128: > 50% survival after 60 days
vehicle
MCLA-128
T + P
vehicle
MCLA-128
T + P
MCLA-117 (CD3 x CLEC12A)KEY FACTS – DATA - DIFFERENTIATION
20 May 2015
NON-CONFIDENTIAL
Tumor (stem) cell
CD3
20 May 2015
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 IgG-like dosing schedules; attractive clinical development
superior to antibody fragments; eligible for Orphan Drug Designation ( EU/US); high chance of break-through designation (FDA);
Unique mode of action retargeting T cells via novel AML target with restricted tissue expression; kills tumor (stem) cells
NON-CONFIDENTIAL
T cell AML blastFirst-in-Human Study:
Q1, 2016
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
20 May 2015
CLEC12A – RESTRICTED TISSUE EXPRESSION
NON-CONFIDENTIAL
100
75
50
25
0AML BM Normal BM
% C
LEC
12
AC
D3
4+C
D3
8-
cells
%
rBM
CLEC12A expression on AML stem cells
20 May 2015
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
NON-CONFIDENTIAL
CFSE
Ctrl IgG
CD3 IgG
TT x CD3
Ctrl Biclonics®
MCLA-117
Biclonics®
Total T cells CD8 T cellsCD4 T cells
Ctrl IgG
CD3 IgG
CD3xTTctrl Biclonics®
MCLA-117Biclonics®
Total T cells CD4 T cells CD8 T cells
CSFE
cou
nts
T cell AML blast
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
20 May 2015
MCLA-117 EFFICACY IN PRIMARY AML MATERIALS (I)
NON-CONFIDENTIAL
CLEC12A
Isotype
CLEC12A expression on AML blasts
CD3
CD
34
CD3
CD
34
Day 0
Day 10ctrl Biclonics®
Day 10 MCLA-117
93%
5%
81%
16%
1%
96%
T cell expansion
Tumor cell killing
Biclonics® for immunomodulationUNCOVERING THE RIGHT TARGET COMBINATIONS FOR DIFFERENTIATING THERAPEUTICS
20 May 2015
NON-CONFIDENTIAL
Breakthrough of the Year
2013
Time
Ove
rall
surv
ival
control
Immunotherapy combinations
standard of care
immunotherapy
Improving survival of cancer patients
‘Lifting the curve’
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
20 May 2015 NON-CONFIDENTIAL
BICLONICS® IN CANCER IMMUNOTHERAPY
T cell
PD-1
TIM-3
CTLA-4
LAG-3
BTLA
VISTA
OX40
CD28
GITR
CD137
CD27
HVEM
? ?agonistic blocking
PD-1 x TIM-3
PD-1 x OX-40
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
20 May 2015 NON-CONFIDENTIAL
BISPECIFIC - MONOVALENCY
combination A B
tumor + +
normal + -
Tumor cell
Normal cell
overexpression A B
tumor +++ +
normal + +
Normal cell
Tumor cell
targeting A B
tumor +++ +
normal + +
T cellTumor
cell
favorable toxicity profile compared to a combination of antibodies ??
20 May 2015
A UNIQUE MODULAR DISCOVERY STRATEGY
PD-1 centric
NON-CONFIDENTIAL
BBB
TIM-3 AAA
CCC
iMOD targets
ZZ
EGFR ZZ
ZZ
RTK targets
PD-L1 centric
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)
Reporter cell line
Exhausted T cells
(HIV, Miha)
TILS
Lead
Functional screens
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
20 May 2015 NON-CONFIDENTIAL
HIGHLIGHTS
T cell AML blast
Tumor cell
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 tumorcell killing
An extremely attractive investment opportunity
Thank you for your attentionTON LOGTENBERG
CEO
20 May 2015
NON-CONFIDENTIAL
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