December 2017 1 Combining Bi-specific Antibodies and Oncolytic Virus Therapy Shautong Song, MD. Ph.D.
December 2017
1
Combining Bi-specific Antibodies and
Oncolytic Virus Therapy
Shautong Song, MD. Ph.D.
2
Company Overview
Product Technology IndicationResearch IND
EnablingIn vitro In vivo
TEA-OV Candidates
IKT-901 FAP-TEA-VV Solid tumors
IKT-902 EpCAM-TEA-VV Solid tumors
IKT-903 EphA2-TEA-VV Solid tumors
IKT-904 HER2-TEA-VV Solid tumors
IKT-905 GPC3-TEA-VV Solid tumors
IKT-906 GD2-TEA-VV Solid tumors
IKT-907 FAP-TEA-HSV Solid tumors
VV Expressing Checkpoint Inhibitors
IKT-201 PD-L1-VV Solid tumors
IKT-202 PD-1-VV Solid tumors
IKT-203PD-L1-FAP-TEA-
VVSolid tumors
CAR (Chimeric Antigen Receptor)-T: VV Loaded & Next Gen NK
IKT-701 VV-loaded CAR-T Solid tumors
IKT-702 CD19-CAR-NK Blood tumors
IKT-703 GD2-CAR-NK Solid tumors
• BCM spin-off company at JLABS@Houston
• Technology: Oncolytic virus therapies
• Lead Program: T-cell Engager-Armed oncolytic
virus expressing bi-specific antibodies (TEA-OV)
• Short Timeline to Clinic With Lead Program:
ppIND meeting has been held regarding IKT-901,
which is expected to enter Phase I in Q3 2018
• Manufacturing & Trial Execution Leverages
Leading OV Experts: BCM & UPMC experts for
GMP production and trial execution
• Strong IP Portfolio: Robust and growing portfolio
of filed 4 patents
Company Overview & Key Highlights
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3
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Oncolytic Viruses: Validated through recent approvals and multiple strategic
partnerships
Licensor/Acquiror Target
BMS PsiOxus
Pfizer Ignite
Merck Viralytics
Merck DNAtrix
Licensor/Acquiror Target
Boehringer ViraTherapeutics
Pfizer Western Oncolytics
Celgene Oncorus
2004 2006 2008 2010 2012 2014 2016+
BioVex first reports efficacy
of OncoVEX in Phase 2
study for melanoma
Amgen’s T-VEC
was approved by
FDA for melanoma
FDA issued
guidance for OV
clinical trials
BioVex was
acquired by Amgen
for $1 billion
ONYX-015 was
approved by CFDA for
head & neck cancer
>7 OV Deals
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Immuno-oncology: Despite recent advances, limitations remain
Therapy Class Examples%(CR+PR)
LimitationsIKT Approach to Overcome
LimitationsSolid Liquid
Tumor Antigen
mAb
12.2-
32.5%1
• Minimal Immune
Stimulation
• Vaccinia Mediated Oncolysis
• T Cell Stimulation/Recruitment
Bi-specific T cell
Engager88%2
• Side effects
• Suboptimal solid tumor
penetration
• Expression restricted to tumor
• Increase local expression of BiTE
Cytokines 25%3 • Systemic Side effects • Transgene expression limited to tumor
Checkpoint
Inhibitors6-25%4 87%5 • Safety, esp. in combo w/ other
IO• Local expression to avoid systemic effects
DC/CIK Therapy 0%6 • Minimal efficacy to date
• Not an ‘off the shelf’ product• Off the shelf approach
Oncolytic virus 10-26.4%7 • Potency as monotherapy• Armed with I/O potentiation biologics
against multiple unique targets
CAR-T cell therapy Tisagenlecleucel-T 83-95%8
• Safety
• Not an ‘off the shelf’ product
• Efficacy in solid tumors
• CAR-T’s loaded with OV expressing
biologics against solid tumor targets
Sources: 1. McCann et al. Gynecol Oncol. 2012; 127(2); Pietrantonio et al. Oncologist. 2015; 20:1261; Xiong et al. Journal of Clinical Oncology 22:2610.2. http://www.amgen.com/media/news-releases/2015/12/amgen-presents-data-from-three-trials-evaluating-blincyto-blinatumomab-in-acute-lymphoblastic-leukemia-at-ash-2015/3. Buchbinder et al. Journal for Immjunotherapy of Cancer 2016 4:52. https://www.proleukin.com/downloads/24954-Fact-Sheet-and-Questions-for-Your-Doctor-Guide_7-1.pdf4. Kwok et al. Hum Caccin Immunother. 2016:2777; Queirolo et al. Cancer Treat Rev. 2017 19:71; 5.Villasboas et al. F1000 Faculty 2016 5:Rev-7686.Maia et al. Crit Rev Oncol Hematol. 2017 113:2917.Bilsland et al. F100Res 2016 30;58. https://www.fda.gov/downloads/AdvisoryCommittees/CommitteesMeetingMaterials/Drugs/OncologicDrugsAdvisoryCommittee/UCM567385.pdf
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TEA-OV: A novel modality leveraging established IO approaches
Multi-technology approach targeted to novel tumor-specific antigens:
– Oncolytic vaccinia virus expressing bi-specific antibodies
– Targeting FAP, EpCAM, EphA2, HER2, GPC3, and GD2
Superior to other modified VVs:
– Expression and activity does not depend on development of an endogenous
antitumor response (absent/ compromised in many patients)
– Directly engages T cells to kill non-infected tumor cells
– Induces anti-tumor immunity without overdriving innate viral immunity
Addresses limitations of BiTE solid tumor therapy:
– TE continually produced locally within VV-infected tumor translating to
high tumor penetration
– High local TE concentrations reduces the systemic side effects and toxicity
– Viral oncolysis prevents antigen loss variants
Program Highlights
CD3 Ab
Target Ab
Tumor cell
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FAP-TEA-VV: Overview
• Targeting FAP enhances antitumor activity
− Improve virus spread within tumor tissue by
targeting CAF
− Overcome immune suppressive tumor
environment by targeting TAM
− Enhance bystander killing of FAP+ tumor
• FAP-CAR-T and FAP tumor vaccine have
been evaluated in clinical studies
− The safety of FAP-CAR-T therapy is being
validated in phase 1 clinical study
− A clinical study of FAP-IL2 fusion protein
has been launched
FAP-
TEA-VV
FAP+ CAF
CTL
FAP+ TAM
CTL
Tumor
cell
FAP+ Tumor
CTL
Cancer-Associated Fibroblasts: FAP is
overexpressed in stroma of >90% of epithelial
tumors, and is not expressed in healthy adult tissues
outside of wound repair1
Tumor-Associated Macrophages
Tumor Cells:
A B C
A
B
C
Mechanism of Therapeutic Effect
FAP Expression in Tumor Environment
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PROBLEM: Spread of Virus Limited by Tumor Environment
The antitumor effects of systemic delivery of vaccinia virus is limited by its low virus delivery
efficacy (limited virus access to tumor), and suboptimal virus spread within the tumor tissue
Role of Cancer associated Fibroblasts:
• CAFs produce collagens, laminins, fibronectins, proteoglycans, and hyaluronan, forming a dense
extracellular matrix (ECM) around tumor cells
• CAFs combined with ECM provide physical barriers to oncolytic viruses, forming a shield surrounding
tumor nests
• Oncolytic viruses have limited autonomous motility and can only be spread through cell-to-cell contact
or soluble diffusion across concentration gradients, both of which can be blocked by CAF and ECM
- First, viruses could potentially adhere to any surfaces of CAFs where they are first administered
and then fail to spread since CAFs are rather resistant to virus infection.
- Second, oncolytic VV has a diameter > 200 nm and physically does not fit through the strands of
the ECM, preventing passive diffusion across concentration gradients to reach the tumor.
IKT’s FAP-targeted virus provides an alternative and unique strategy to improve the efficacy of systemic
administration of oncolytic virus, by promoting virus spread and replication within tumors
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Solution: Targeting the ECM through CAFs
Targeting elements of the ECM improves local replication of systemically delivered virus:
• Using matrix-degrading enzymes to remove physical ECM barriers is currently the foremost option as
a study of HSV (a large virus over 100 nm) showed that coinjection of matrix-degrading collagenase
improved viral spread within the tumor
• However, CAFs could produce ECMs continuously and thus the efficacy of matrix-degrading
collagenase could rely on the speed of production and degradation of ECMs
• Despite the limited gains, this provides compelling proof of principle to continually target CAFs as a
means to improve systemic efficacy of OVs
FAP-TEA-VV provides an alternative and unique strategy to improve systemic therapy of OV by:
• Destroying CAFs and removing physical barriers to oncolytic virus in a more permanent manner,
• Allowing small amount of virus to replicate effectively within tumor, and leading to enhanced
antitumor effects
We observed that administration of FAP-TEA-VV in mouse models significantly enhanced viral titer
within tumors, leading to enhanced antitumor effects and the increase of viral titer is correlated with
the destruction of FAP-positive stromal cells
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Fibroblast Activation Protein (FAP)
melanoma
Normal
skin
20X 40X
Hofmeister et al; Cancer Immunol Immunother 2006
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FAP-TEA-VV: Construction
CD3 AbFAP Ab
FAP+
Tumor cell
1. Recombinant insertion of TE into TK gene
of ∆VGF-VV
2. Plaque purification (YFP+); YFP deletion
(Cre/loxp)
3. Production of FAP-TEA-VV in permissive
cell lines
Production of Recombinant FAP-TEA VV
vTK -L F17R vTK -RFAP-scFv CD3-scFv
FAP Ab
CD3 Ab
FAP+
Tumor cell
CD3+
T-Cell
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Mouse Version FAP-TEA-VV
FAP-TEA-VV
GM-CSF-VV
VGF
ITR 5’TK
GM-SCFPF17R
VGF
ITR
LacZ
P11K
GFPPSEL P11K
LacZ
3’TK
VGF ITR 5’TK
FAP-TEPF17R
VGF
ITR
LacZ
P11K
DsRedPSEL P11K
LacZ
3’TK
EphA2-TEA-VV
A
B C
M 0.5µg 1µg. 2.5 µg
EphA2-CD3 proteinF
AP
-TE
A-
VV
Ep
hA
2-
TE
A-V
V
GF
P-V
V
VGF
ITR 5’TK
EphA2-TEPF17R
VGF
ITR
LacZ
P11K
DsRedPSEL P11K
LacZ
3’TK
0
10
20
30
40
50
60
0 0.1 1 5
GM
-CS
F e
xpre
ssio
n
(pg/m
l)
MOI
B16
GL-261
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FAP-TEA-VVMedium EphA2-TEA-VV
MOI 1
GFP
48 h
T cells
GL261-
mFAP 24 h 42.2%
61.0%
30.4%
16.4% 0.67%
37.4%
32.8%
EphA2-TEA-VV FAP-TEA-VV
MOI 0.1
28.6%
19.1%
1.67%
FAP-TEA: Enhanced in vitro Killing with T cells
FAP-TEA-VVMedium EphA2-TEA-VV
MOI 1
GFP
48 h
T cells
GL261-
mFAP 24 h 42.2%
61.0%
30.4%
16.4% 0.67%
37.4%
32.8%
EphA2-TEA-VV FAP-TEA-VV
MOI 0.1
28.6%
19.1%
1.67%
GFP Expressing
FAP+ Target Cells
MOI- multiplicity of infection (measure of virus concentration in assay)
T c
ell
Activa
tio
n M
ark
ers
0
2000
4000
6000
8000
Me
diu
m
Ep
hA
2-T
EA
-VV
FA
P-T
EA
-VV
mIF
N-γ
p
g/1
06
T c
ells
MOI 1
MOI 0.1
0
500
1000
1500
2000
Me
diu
m
Ep
hA
2-T
EA
-VV
FA
P-T
EA
-VV
mIL
-2 p
g/ 1
x1
06
T c
ells MOI 1
MOI 0.1
0
2000
4000
6000
8000
Me
diu
m
Ep
hA
2-T
EA
-VV
FA
P-T
EA
-VV
mIF
N-γ
p
g/1
06
T c
ells
MOI 1
MOI 0.1
0
500
1000
1500
2000
Me
diu
m
Ep
hA
2-T
EA
-VV
FA
P-T
EA
-VV
mIL
-2 p
g/ 1
x1
06
T c
ells MOI 1
MOI 0.1
Tumor cells
Murine Construct
A B
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FAP-TEA-VV: Bystander Killing of Tumor Cells
Grow VV (FAP or Control)
in Tumor cells
Harvest culture medium
(no infected cells present)
Add to FAP+ cells
w/ T cells
Murine Construct
Experiment Design Results
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FAP-TEA-VV: Inhibition of B16 Tumor Growth
FAP-TEA-VV demonstrates robust tumor inhibition in the B16 tumor model
0 1. Implant 1x106 B16
cells in right flankC57BL/6
4
Day
7
23
2. Implant 5x104 B16
cells in left flank
3. PBS or 1x108 PFU
VV into right flank
Experiment Design
Right Flank Left Flank
Days post tumor cell implantation
D5 D7 D9 D11D0 D13 D15 D17 D19 D21 D23
Days post tumor cell implantation
D3 D5 D7 D9D0 D11 D13 D15 D17 D19
Tu
mo
r V
olu
me
(mm
3)
Tu
mo
r V
olu
me
(mm
3)
2500
2000
500
1500
1000
0
2500
2000
500
1500
1000
0
Results
FAP-TEA-VV inhibited growth of primary and secondary tumors
PBS
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FAP-TEA-VV: Inhibition of Tumor Metastases in vivo
FAP-TEA-VV inhibits surface metastases and tumor growth in the B16 tumor model
0
50
100
150
200
PB
S
Eph
A2-
TEA
-VV
GM
CS
F-V
V
FAP
-TE
A-V
V
Mea
n #
of S
urfa
ce
Met
asta
ses
B
*
2x105
B16 i.v.
C57BL/6
1Day 0
PBS or 1x108 PFUs
VV i.v.
3 15
A
PBS
EphA2-
TEA-VV
GM-CSF
-VV
FAP-
TEA-VV
sacrifice and
harvest lungs
CExperiment Design
0
50
100
150
200
PB
S
Eph
A2-
TEA
-VV
GM
CS
F-V
V
FAP
-TE
A-V
V
Mea
n #
of S
urfa
ce
Met
asta
ses
B
*
2x105
B16 i.v.
C57BL/6
1Day 0
PBS or 1x108 PFUs
VV i.v.
3 15
A
PBS
EphA2-
TEA-VV
GM-CSF
-VV
FAP-
TEA-VV
sacrifice and
harvest lungs
C
0
1. Intravenous injection of
2x105 B16 cellsC57BL/6
1
Day
3
15
2. Inject PBS or 1x108
PFUs VV
3. Sacrifice and harvest lungsM
ean #
of
Surf
ace
Met
asta
ses
FAP-TEA-
VV
GM-CSF-
VV
EphA2-
VV
PBS
Results
Inhibition of Tumor Metastases
In the same tumor
model, FAP-TEA-VV
inhibited tumor
metastases compared
to virus alone
Murine Construct
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FAP-TEA-VV: T cell infiltration in vivo
Murine Construct
anti-CD3 DAPI Merge
PBS
EphA2-
TEA-VV
GM-CSF
-VV
FAP-
TEA-VV
C
A B
NS
P < 0.05
P < 0.01
NS
P < 0.05
P < 0.01
%ofCD
8+tum
orinfiltratingcells
PBSEphA2- GM-CSFFAP-TEA-VV-VVTEA-VV
%ofCD
4+tum
orinfiltratingcells
PBSEphA2- GM-CSFFAP-TEA-VV-VVTEA-VV
anti-CD3 DAPI Merge
C
B16 subcutaneous tumor model
3 intratumor VV injections (D7, D10,
D13), Tissue harvest and assay (D15)
A&B) Infiltrating T cells by flow
cytometry
C) Infiltrating T cells by fluorescent
microscopy
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FAP-TEA-VV: T cell activation in vivo
Murine Construct
B16 subcutaneous tumor model
3 intratumor VV injections (D7, D10,
D13) Tissue harvest and assay (D15)
D) Intracellular staining of tumor
infiltrating T cells
E) ELISPOT IFNγ of splenic CD8+ or
CD4+ T cells against dendritic cells
presenting FAP or TRP2 (a B16
tumor antigen)E
0
50
100
150
200
250
300
Me
diu
m
Ep
hA
2-T
EA
-VV
GM
-CS
F-V
V
FA
P-T
EA
-VVS
FC
pe
r 5
x1
04
CD
8+
T c
ells
Medium
DC-Lv-contr.
DC-FAP-Lv
DC-TRP2-Lv
0
40
80
120
160
Me
diu
m
Ep
hA
2-T
EA
-VV
GM
-CS
F-V
V
FA
P-T
EA
-VVS
FC
pe
r 5
x1
04
CD
4+
T c
ells
Medium
DC-Lv-contr.
DC-FAP-Lv
DC-TRP2-Lv
P <0.05P <0.05
PBS EphA2-TEA-VV GM-CSF-VV FAP-TEA-VV
CD4-PerCP
IL-2
CD8-PE
IFN
-γ
FSC
SS
CD
0%
0%
1.14% 6.36% 12.3%
7.35% 10.9% 9.58%
D
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FAP-TEA-VV: Correlation of Stromal Destruction & Virus Spread
Anti-FAP DAPI Merge
PBS
EphA2-TEA-VV
GM-CSF-VV
FAP-TEA-VV
A
0
5
10
15
20
PB
S
Ep
hA
2-T
EA
-VV
GM
-CS
F-V
V
FA
P-T
EA
-VV
% F
AP
+ c
ells
B **
0
5
10
15
20
PB
S
Ep
hA
2-T
EA
-VV
GM
-CS
F-V
V
FA
P-T
EA
-VV
VV
tite
r(x
10
8P
FU
s/g
tissue)
C
0
5
10
15
20
0 4 8 12 16
%F
AP
+ c
ells
VV titer (x108 PFUs/g tissue)
PBS
EphA2-TEA-VV
GM-CSF-VV
FAP-TEA-VV
D
**
Murine Construct
B16 subcutaneous tumor model
3 intratumor VV injections (D7,
D10, D13). Tissue harvest and
assay (D15)
A) Fluorescent microscopy of
FAP+ cells
B) % of FAP+ cells in tumor tissue
C) VV titer per gram of tumor
tissue
D) Relationship between FAP+
cells and VV titer
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FAP-TEA: mTEA-VVs have no systemic anti FAP activity
Murine Construct
B16 s.c. & i.v. tumor model
Serum was collected from mice treated with
PBS or GFP-VV or EphA2- TEA-VV or
mFAP-TEA-VV for both i.v. and s.c. models
(n = 5). Supernatant was collected from MC-
38 cells infected with GFP-VV or EphA2-
TEA-VV or mFAP-TEA-VV at MOI 5 for 24
h. Supernatant served as positive control
Medium served as negative control. GL-261-
FAP-GFP cells were co-cultured with Con A-
activated mouse splenocytes in presence of
supernatant or serum for 24 h. The killing
activity was analyzed by flow cytometry
GFP Expressing
FAP+ Target Cells
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FAP-TEA: TEA-VV Does Not Affect Bone Marrow Cellularity or Mouse Weight- metastatic B16 model
Murine Construct
mFAP-TEA-VVs do not affect the total cell number of mice bone marrow and mice weight in systematic metastasis B16 model. 2 × 105 B16 cells
were i.v. injected through tail vein of C57/BL6 mice (n = 5). The mice were injected 1 × 108 VV through tail vein on day 1 and 3. (a) On day 15,
bone marrow was collected for counting of total bone marrow cell numbers. (b) Mice body weights were monitored at the different time points
A B
• Complete Phase I/II trials
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R&D BCM/CAGT
2013 2014 2015 2016 2017 2018-2019 2020+
Provisional Patent Angel Round
Joined JNJ JLABS Incubator
3 Additional Patents Filed IND Application
Phase I StudyIND Enabling Studies
• Licensed TEA-VV patent from BCM & filed 3 additional patents
• IKT is working with Novella to file IND application in 2018
• IKT’s lead product (clinical grade VV) will be produced in Q4 2017
2015-2017
• Initiate phase I studies (IT/IV injection) in USA in Q2 2018
2018-2019
2019+
Rationale for FAP-targeted VV therapy
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Limitations HSV-GMCSFVV-GMCSF
(Wyeth Strain)
FAP-TEA-VV
(WR Strain)
Tumor Stroma ▼Limits viral spread/oncolysis
▼Limits viral spread/oncolysis
▲Targeted by FAP-TE, enhancing viral spread/oncolysis
Endogenous anti-Tumor T cell
Required▲Enhanced by GMCSF
Required▲Enhanced by GMCSF
▲Not required▲TE redirects any T cell to target
Anti-viral Immunity ▼Enhanced by GMCSF
▼Enhanced by GMCSF
▲Anti-viral T-cells may be redirected to antigen target
Immune Suppressive MDSCs
▼Enhanced by GMCSF
▼Enhanced by GMCSF
▲Targeted by FAP-TE
Infectious Spread Receptor mediated ▲Efficient cell-cell▼Limited by CAF
▲Efficient cell-cell▲Enhancing spread through CAF
Viral Replication ▼Requires nuclear translocation
▲In cytoplasm within 2 hours
▲In cytoplasm within 2 hours
Shautong Song, MD/PhD
CEO, Icell Kealex Theapeutics
JLABS@TMC
2450 Holcomb Blvd J206, Houston, TX 77021
www.icellkealex.com
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For more information, please contact:
Thank You!!!