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Anil Singhal, President and CEO June 2019
Off-The-Shelf, Engineered Gamma Delta γδ T cell Therapy for Oncology
Adicet Bio: Two Compelling Platforms for Cell Therapy
2
• Founded in 2015 with $51M Series A funding - 60 employees
• Potent off-the-shelf, engineered γδ T cell therapy for oncology and other indications
• Proprietary intracellular tumor-selective targets from TCR-L platform for treatment of solid tumors
• IND for ADI-001 planned in Q4’19 for non-Hodgkin’s lymphoma and CLL
• Robust, cost-effective, cGMP-compliant manufacturing from healthy donors
• Strategic collaboration with Regeneron
• Experienced leadership team and top tier investors
Leading the Next Generation of CAR-T Therapies
Our Goal: Improve Cancer Immunotherapy
3
• Autologous CAR-T have demonstrated remarkable efficacies in heme malignancies, however..
• Cumbersome, high manufacturing cost of patient-specific therapies
• Current therapies are compromised by patient’s immune system dysfunction
• Existing cell therapies present challenging safety profiles
• Loss of target from current cell therapies leading to relapses
• Unsuccessful treatment of solid tumors due to lack of selective targets
Engineered γδ T Cells Solve Key Challenges of Current Cellular Therapies
Adicet Advantages
4
γδ T Cells: The Foundation of Superior ‘Off-The-Shelf’ T Cell Therapies
• Allogeneic without gene editing
• Bind tumor antigen without MHC complex
• Highly potent against solid and liquid tumors
• Provide both innate and adaptive immunity
• No risk of GvHD
• Actively traffic to solid tumors and tissues
• Potent γ-IFN production
• Able to redose on demand
NCRs
DNAM-1
NKG2D
Engineered TCR(defined specificity)
Engineered CAR (defined specificity)
γδ T cell
γδTCR
γδ T cells express multiple tumor-recognizing receptors
5
Godder et al. 2007 Meraviglia et al. 2017
Improved Disease Free ProgressionColorectal Cancer
γδ T cell hi
γδ T cell lo
γδ T cell hi
γδ T cell lo
γδ T cell lo / IFNγ lo
Pan-Cancer: Improved Overall Prognosis
Gentles et al. 2015
Post-HSCTImproved Survival
Overall Survival
Improving Cancer Immunotherapy
γδ T Cells Strongly Correlate with Positive Clinical Outcomes
Building a Broad Pipeline in Cancer
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Program Indication Discovery Target Optimization
Preclinicalγδ cells
Manufacturing & IND-enabling
studies
InitiatePhase 1
CD20 NH Lymphoma IND filing 4Q’19 1Q’20
UT1 Melanoma
UT2 Solid Tumors
UT3 Multiple Myeloma
UT4 Solid Tumors
UT5 Prostate Cancer
UT6 Solid Tumors
ADI-001
UT: Undisclosed Targets Derived from TCR-L platform
ADI-001 Cells Potently Kill Multiple Lymphoma Cell Lines in vitro
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• Innate and CAR-mediated activity of γδ T cells is superior to published results of competitor products
• CD20 CAR potentiates innate tumor recognition and killing
• Effective killing of HLA-Class 1 null (Daudi) cells
• Effective killing of cell lines expressing low CD20 levels
Raji*(~54,000 CD20 /cell)
Daudi*(>50,000 CD20 /cell)
Mino*(>90,000 CD20/cell)
WILL-2*(<1000 CD20 /cell)
CD20 CAR Vδ1 cells Un-engineered Vδ1 cells* Adicet Study
0.001 0.01 0.1 1 10 100
0
25
50
75
100
-25
0
25
50
75
100
Effector: Target Ratio
0.001 0.01 0.1 1 10 100
0
25
50
75
100
0
25
50
75
100
Effector: Target Ratio
0.001 0.01 0.1 1 10 100
0
25
50
75
100
0
25
50
75
100
Effector: Target Ratio
% C
ytot
oxic
ity
0.001 0.01 0.1 1 10 100
0
25
50
75
100
0
25
50
75
100
Effector: Target Ratio
y
y
-5 0 5 10 15 20 25 30 350
1×1010
2×1010
3×1010
4×1010
5×1010
6×1010
7×1010
Mea
nTo
tal F
lux
(p/s
) +/-
SE
M
ADI-001 Cells Effectively Control Aggressive Lymphoma Tumors in Mice
• γδ T cell treatment initiated* at T=0, s.c. tumor volume ≥ 200mm3
• 2nd generation CD20 CAR-modified γδ T cells effectively control multiple disseminated (iv) and localized (sc) tumors
-5 0 5 10 15 20 25 300
1000
2000
3000
4000
5000
Days Post Treatment
Mea
n Tu
mor
Vol
ume
(mm
3 ) +/
- S
EM
Subcutaneous Raji Tumor Growth*
* Adicet Study
Intravenous Granta Tumor Growth*
-5 0 5 10 15 20 25 30 35 400
1000
2000
3000
4000
()
Subcutaneous Mino Tumor Growth*
Mea
n Tu
mor
Vol
ume
(mm
3 ) +/-
SEM
-5 0 5 10 15 20 25 30 35 40 45105
106
107
108
109
1010
1011
1012
Days Post Treatment
Mea
n To
tal F
lux
(p/s
) +/-
SE
M
Intravenous Raji Tumor Growth*
**
* *
Subcutaneous Raji Tumor Growth*
ADI-001 Cells Effectively Control Secondary Challenge Tumors
• Control of secondary tumor challenge strongly indicates persistence, potency & lack of exhaustion
1o Tumor Challenge 2o Tumor Challenge
Mice with no / low tumor burden at Day 55-60 were rechallenged with tumor
* Adicet Study
0 20 40 60 80 1000
1000
2000
3000
4000
5000
6000
Days Post Treatment
Mea
n Tu
mor
Volu
me
(mm
3 ) +/-
SEM
CD20 CAR γδ T Cells Proliferate in Response to Activation in Tumors
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Blood
Spleen
Liver
Bone marrow
Tumor
Cel
l Num
ber
T cell Proliferation
Day 2 Post-treatmentCAR-T γδ
Substantial target-mediated proliferation of CD20 CAR γδ T cells in localized lymphoma tumors at 6 days post treatment
CD20 CAR γδ T Cells Proliferate in Response to Activation in Tumors
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Blood
Spleen
Liver
Bone marrow
Tumor
Cel
l Num
ber
T cell Proliferation
Day 2 Post-treatmentCAR-T γδ
Day 6 Post-treatment CAR-T γδ
Substantial target-mediated proliferation of CD20 CAR γδ T cells in localized lymphoma tumors at 6 days post treatment
T cell Proliferation
CD20 CAR γδ T Cells Proliferate in Response to Activation in Tumors
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Blood
Spleen
Liver
Bone marrow
Tumor
Cel
l Num
ber
T cell Proliferation T cell Proliferation
Day 2 Post-treatmentCAR-T γδ
Day 6 Post-treatment CAR-T γδ
Day 6 Post-treatment CAR-T αβ
Substantial target-mediated proliferation of CD20 CAR γδ T cells in localized lymphoma tumors at 6 days post treatment
Blood
Spleen
Liver
Tumor
Bone marrow
T cell Proliferation
• No GvHD observed in mice treated with γδ cells
• No gene editing required to overcome GvHD
• Deaths in the αβ CAR T cell group due to GvHD
Intravenous Raji Tumor in SRG-15 Mice†*
Absence of GvHD with ADI-001 Cells
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αβ CART cells CAR γδ T cellsTumor alone
Days Post Treatment Pe
rcen
tage
Sur
vivi
ng
0 2 0 4 0 6 0 8 00
2 5
5 0
7 5
1 0 0
†SRG-15 mice express human IL-15 transgene* Adicet study
• Robust activation using Adicet’s γδ TCR mAbs
• Viral transduction
+
Selection of Optimal Healthy Donors Manufacturing Process < 1 Month Batch Sizes of 2E11 Cells
• Large-scale closed-system perfusion bioreactor-based expansion
• Excellent post cryopreservation viability & function
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~1000s of doses per batch
Able to selectively expand different γδ T cell subsets
Simplify for Robustness, Partner for Capability and Capacity
Adicet Advantages: Robust, Large-Scale Manufacture of γδ T Cells
Clinical Development of ADI-001
• Target product profile of ADI-001 (CD20 CAR γδ T cells derived from healthy donor)⎼ Highly effective (ORR, PFS/OS) in CD20 expressing NHL and CLL
⎼ No GvHD
⎼ Significantly lower CRS
• Phase 1 Study⎼ NHL, CLL patients relapsing from 2 or more prior lines of treatment
⎼ 2-3 cohorts for dose escalation/safety
⎼ Up to 30 patients at the selected dose
⎼ Single treatment with ADI-001
• Pivotal study likely in DLBCL and/or MCL
ADI-001 Timeline
GMP Manufacturing initiated: 4Q’18
Pre-IND meeting Q1’ 2019
• IND filing: 4Q’19
• Phase 1 initiation: 1Q’20
• Clinical data: 1H’21
16
TCR-Like monoclonal antibodies (TCRL)
17
Adicet Advantages: Unlocking the Intracellular Proteome
18
CHALLENGE
SOLUTION
• Lack of disease-specific cell surface targets in solid tumors (80% of proteins are intracellular)
• Ability to target disease-specific intracellular proteins highly expands the target pool
• Unlikely to express on normal cells• TCR-Like (TCR-L) antibodies are specific to
peptide-MHC complexes and have multiple applications– Mimic TCR specificity with mAb affinity– scFv for chimeric antigen receptors for cellular
therapy– Bispecific T-cell engaging antibodies
Tyrosinase TCR-Ls Effectively Control Melanoma Growth
19
• Tyr CAR γδ T cells effectively controls subcutaneous growth of melanoma cell line
• Tyr-CD3 bispecific antibodies effectively control subcutaneous growth of melanoma cell line
Mea
n Tu
mor
Vol
ume
(mm
3) +
/-SE
M
- 1 0 -5 0 5 1 0 1 5 2 0 2 5 3 00
5 0 0
1 0 0 0
1 5 0 0
2 0 0 0
2 5 0 0
Tyr CAR γδ T cells
Tumor alone
Day Post Treatment
WM266.4 Tumor Growth in NSG Mice*
* Adicet StudyM
ean
Tum
or V
olum
e (m
m3)
+/-
SEM
WM266.4 Tumor Growth in NSG Mice*
Tumor alone
Tumor alone + PBS
Tumor + Tyr-CD3 bispecific 1
Tumor + Tyr- CD3 bispecific 2
Tumor + irrelevant bispecific
2000
1500
1000
500
00 5 10 15 20 25 30
Day
Additional Opportunities for Adicet Platform Technologies
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• Potential to treat severe infectious disease with γδ T cells
• Potential to eradicate autoreactive B-cells with CAR γδ T cells
• Growing portfolio of internally-validated tumor-specific TCR-like antibody targets
– Able to develop TCR-like antibodies as T cell engaging antibodies
Strong IP Portfolio: 11 Patent Families Worldwide
Patent portfolio on γδ T cell technologyComposition of matter for engineered γδ T cells
Selective expansion of γδ T cell populations and compositions thereof
Family of patents on TCRL technologyTCRL technology and use in cancer, viral infection, and autoimmune disease
Specific TCRL Antibodies and their targets
Class I major histocompatibility complexes
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Key Terms of the Collaboration with Regeneron in Oncology
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Structure of the agreement: • Multiple targets • REGN has option to license a defined number of product
candidates at IND̶ REGN optioned products: Adicet has option to co-
develop/co-commercialize OR receive royalties
• Adicet products: royalties to REGN
γδ T cells engineered with CARs and TCRs for oncologyGenerate a pipeline of liquid and solid tumor product candidates
Five year research collaboration; Initiated 7/2016
Adicet: Leader in CAR and TCR Engineered γδ T cells
Company γδ Subtype Engineering Partner Stage (engineered ACT)
Vδ1
Adicet δ1 CAR/TCR Regeneron FPI 1Q2020
Gamma Delta/Lymphact δ1 no Takeda preclinical
TC Biopharm δ1 not clear UDublin (2019) FPI 2H2019?
non-
Vδ1 Adicet δ2, δ3 CAR/TCR Regeneron FPI 2020
TC Biopharm δ2 CAR bluebird bio Ph 1Incysus δ2 TMZ-R UAlabama FPI 2H2019
Immatics δ2 TCR MDACC preclinical
• Other players, not directly competing with Adicet, include: Gadeta (αβT, autologous), Phosphogam (Vδ2), American Gene Technologies (viral activation of Vγ9Vδ2 cells), potentially Universal Cells/Adaptimmune
Experienced Team with Proven Track Record
24
Stewart Abbot, Ph.D.Chief Scientific and Operating Officer
Brian HoganChief Financial Officer
Anil Singhal, Ph.D.President and CEO
Investment Opportunity
25
• Potent off-the-shelf, engineered γδ T cell therapy for oncology and other indications
• Proprietary targets derived from TCR-L platform for treatment of solid and liquid tumors
• Robust, cost-effective, cGMP-compliant manufacturing from healthy donors
• IND for ADI-001 planned in Q4’19 for non-Hodgkin’s lymphoma and CLL
• Strategic collaboration with Regeneron
• Experienced leadership team and top tier investors
Leading the Next Generation of CAR-T Therapies
Back up
C o n f i d e n t i a l U s e O n l y26
Engineered γδ T Cell Product Development Timeline
27
Program Indication 2019 2020 2021 2022 2023 2024
ADI-001 NH Lymphoma
ADI-002 Oncology
ADI-003 Oncology
Phase 1
Phase 2 / Pivotal BLA filingIND
Preclinical
Phase 1IND
IND
Phase 1
Preclinical
Phase 2 / Pivotal
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