Tumor Immunotherapy with BiTEs

Report
Treating Cancer with T CellEngaging Antibodies
Flavius Martin M.D.
Vice President Research, Amgen Inc.
T cell Tumor Immunotherapy Players
Tumor Cell Antigens:
- Surface/Presented
BiTE®
- Cell autonomous functions
T cells:
- Response tuning
- Effector function
For Internal Use Only. Amgen Confidential.
2
BiTE®
Engineering an Adapter From Two Monoclonal
Antibodies
BiTE® = Bispecific T Cell Engager
Tumor Cell-specific
Antibody
BiTE®
T Cell-specific Antibody
Single-chain Antibody 1
VH
VH
VL
VL
Linker
Single-chain Antibody 2
3
BiTE® Antibodies May Circumvent
Frequent Escape Mechanisms
Any T Cell
CD3e
Do not Require T Cell Clone With Specific T Cell Receptor
Do not Require MHC Class I and
Peptide Antigen for Recognition by T Cell
Can Make Any T Cell Recognize a Surface Antigen
TCR
X
X
BiTE®
Antibody
CD19
EpCAM
CEA
PSMA
Tumor Cell
4
A549 Lung Cancer Cells Peacefully Coexist
With T Cells
Cancer Cell
Resting
CD8+ T Cell
A549 Lung
Cancer Cell:
T Cell Ratio = 1:1
5
Each T Cell Can Kill Nearby Cancer Cell After
BiTE® AMG 110 Is Added
Apoptotic
Cancer Cell
T Cell
Alive Cancer
Cell
-EpCAM
-CD3
6
Kinetic Analysis of in-vitro BiTE® Reaction With
Unstimulated T Cells
AMG 330 = CD33/CD3-bispecific BiTE®; unstimulated human PBMC as effector cells at 10:1 ratio
T cell potency increases
over time by 1-2 logs
28h
Complete lysis
22h
16h
10h
AMG 330 [
7
Unstimulated T cells
show lag phase before
they start killing
Most Subpopulations of T Cells Can Contribute
to Lysis by BiTE in vitro
Kischel, R. et al., poster at AACR 2009
Relative Potency of
Redirected Lysis
T Cell Populations Studied
Marker
CD8+ Bulk
CD8+
+++
CD8+ Naïve
CD28+ / CD45RA+
-/+
CD8+ EM
CCR7- / CD45RA-
++++
CD8+ EMRA
CD28- / CD45RA+
+++++
NKT Cells
CD3+ / CD56+
++
g/d T Cells
CD3+ /b -
+
CD4+ Bulk
CD4+
++
CD4+ Naïve
CD4+ / CD45RO-
-/+
CD4+ EM
CCR7- / CD45RA-
+++
CD4+ EM+CM
CD4+ / CD45RA-
++
CD4+ Naïve, Stimulated
CD69, CD25
+++
CD4+ EM, Stimulated
CD69, CD25
+++
8
Blinatumomab (AMG 103), a CD19/CD3bispecific BiTE® Antibody
• Murine antibody construct of 55 kDa produced by CHO cell-based
process
• CD19 target is diagnostic marker for B cell malignancies
– 100% of ALL cases are positive for CD19
– Expressed on leukemic stem cells with self renewal capacity
– CD19 is activator of PI3 kinase
• Serum half life of AMG 103 is 1-2 hours  continuous i.v. infusion using
port/minipump
• Multiple clinical trials in adult and pediatric ALL patients; NHL experience
N
KD = 10-9 M
-CD19
KD = 10-7 M
-CD3
9
C
CD19-BiTE - Response and HSCT
n/N
95 % CI
Primary endpoint
CR/CRh during the first two cycles
81 / 189
43%
36–50
Exploratory endpoints
MRD response during the first two cycles
CR/CRh
60 / 73
82%
72–90
CR, complete remission; CRh, complete remission with partial hematological
recovery of peripheral blood counts; MRD, minimal residual disease (< 10-4)
Activity of Blinatumomab in NHL Patients Is Dosedependent (Phase 1 Study AMG 103-104)
12x higher dose needed for tumor
Peripheral T Cell Redistribution
Complete and Sustained B Cell Depletion
Bone Marrow Clearance; First PR/CR
High RR
0.5
5
1.5
15
30
60
Dose Levels Tested [µg/m2/Day]
11
90
Preliminary Learnings From Blinatumomab
Monotherapy about BiTE® Modality
• Need only very low doses
– High response rates in ALL patients at steady state serum levels of
0.5 to 1 ng/ml (<18 pM); cumulative doses of low milligrams per cycle
• Eliminates proliferating and nonproliferating target cells
– Potential to eliminate dormant cancer stem cells
• Activity in many locations of body
– Antitumor activity seen in blood, bone marrow, lymph nodes, spleen,
lymphoma tissue, liver tissue
• Activity in patients who have exhausted all established
therapies, including rituximab regimen and SCT
• Activity in elderly and pediatric patients
• Activity in severly immunocompromised patients
– Observed complete response in patients with low to undetectable
peripheral T cell counts
12
Other BiTE® Antibodies in Development
Clinical Phase 1:
• Solitomab (AMG 110: EpCAM) – Advanced solid tumors
• AMG 212 (BAY2010112: PSMA) – Prostate cancer
• AMG 211 (MEDI-565: CEA) – Advanced GI cancers
Pre-clinical:
• AMG 330 (CD33) – Acute myeloid leukemia (AML)
• Multiple myeloma BiTE -• Solid tumor BiTE® –
13
Extending Immunotherapy Response and Utility
Liquid tumors
Naked Antibodies
Solid tumors
Antigens
T cell modulators
ADCs
ADCs
BiTEs
BiTEs
Tumor antigens
Biodistribution
Combos
Antigens
Longer half life
Combos
T cells
TCR-derived constructs Intracellular antigens
T cellular therapies
T cellular therapies
Vaccines
14
Appendix
15
Blinatumomab
28 μg/day
cIV infusion
4 weeks on,
2 weeks off
cIV infusion
4 weeks on,
2 weeks off
Up to 2 cycles
Up to 3 cycles
Primary
endpoint
assessment
Consolidation
Study Endpoints
HSCT Offered to Patients in CR/CRh
(up to 24 months)
Blinatumomab
28 μg/day*
Follow-up
Screening and Enrollment
Confirmatory Open-label, Single-arm,
Multicenter Phase 2 Study
Primary
• CR/CRh during the first two
cycles
Secondary included
• CR, CRh
• Relapse-free survival
• Overall survival
• HSCT realization
• Incidence of adverse events
Exploratory included
• Minimal residual disease
response by PCR during the
first two cycles
*Only cycle 1, days 1 to 7: 9 μg/day
CR, complete remission; CRh, complete remission with partial hematological recovery of
peripheral blood counts (platelets > 50,000/μl and ANC > 500/μl)
cIV, continuous intravenous; HSCT, hematopoietic stem cell transplantation
Probability of Overall Survival
CD19-BiTE in ALL - Overall Survival
1.0
Overall Survival
N=189
0.8
Median OS, months
0.6
95% CI, months
0.4
4.2–7.5
0.2
0
0
2
Patients at Risk
189
139
Probability of Overall Survival
6.1
4
6
8
10
Months
12
14
16
18
104
72
44
27
21
10
6
0
1.0
20
Overall Survival
Landmark Analysis Day 77*
0.8
CR/CRh No CR/CRh
N=79
N=50
Median OS, months
9.9
2.7
95% CI, months
6.8–NE
1.6–4.5
0.6
0.4
0.2
0
0
2
4
6
8
12
14
16
Patients at Risk
79
68
50
26
10
Months
43
15
33
9
21
5
12
4
8
2
5
1
0
0
*After two treatment cycles
NE, not estimable
18
20

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