Optimal-affinity T cell receptors
from humanized TCR mice Elisa Kieback, May 2017
Immunotherapy for Cancer
Cancer-specific receptors
TCR gene therapy
Cancer patient
Cancer-specific T cell
Cancer-specific receptor
T cell
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CASH
BILLS
PROBLEM
NOT EFFICIENT STRATEGY NOT SAFE DMF4
DMF5 CEA
p53
MAGE-A3 MAGE-A3a3a
DMF5
???
HBV
gp100
MAGE-A10
Phase I/IIa
Phase IIb
CARs TCRs
• CD19 CAR T cells: success story for leukemia/lymphoma
• Up to 90% complete remission in end-stage patients
• Target only cell surface antigens
• „Breakthrough Therapy“ designation by FDA
• Employ natural T cell signaling • Target also intracellular
antigens • Target microenvironment • More efficient for solid tumors
How do we find TCRs that are safe and efficient?
MAGE-A4
1D3 WT1
HPV E7 HPV E6
Tyr
gp100
mNY-ESO
NY-ESOc259
Technology – Humanized TCR Mouse
yHuTRA (~1400 kb)
Vα1...41 Cα Jα
yHuTRB (~700 kb) Jβ1 Jβ2
Cβ1 Cβ2 Vβ2...30 D1 D2
Human TCR gene loci transgenic mice
HLA-A*02:01 HLA-DR4
IFN-g
Immunization of mice
Mice are optimal TCR factories
• Most tumor-associated antigens (TAAs) are self-proteins
• Deletional tolerance of high avidity T cells in humans
• Many TAAs differ between mouse and human
• More efficient immune response can be elicited in vivo
à BUT: Mouse TCRs are immunogenic in humans
antigen
Characterize immune response in blood
Isolate reactive T clells
MAGE-A1278 a – fetoprotein158 MAGE-A10254 NY-eso157
4.7 0.9 1.1 3.0
CD
8
p/MHC multimer
5‘ LTR TCRβ 3‘ LTR P2A TCRα WPRE Ψ"
Competing technology Efficacy (TCR affinity)
Safety (no off-target toxicity)
Technology (feasibility/robustness)
Humanized TCR mouse
✔Optimal affinity
✔Self-restricted
"
✔Efficient priming TCR selection
Autologous T cells/TILs" ✖ " ✔ ✖ "Allo-restricted T cells" ✔ ✖ " ✖ "Affinity enhancement" ✔ ✖ " ✖ "HLA-transgenic mice" ✔ ✖ " ✔
Differentiation
2/5 mice 8/10 antigens
Highly robust immune response
Example: MAGE-A1 TCR
• Multiple myeloma • Lung cancer (NSCLC) • Melanoma • Breast cancer • Colon cancer • Hepatocellular
carcinoma • ... 0
20
40
% M
AG
E-A
1+ bi
opsi
essingle cells1-5%10-30%40-60%80-100%
13%
MAGE-A1+ plasma cells
(n=137)
Efficacy
RP
MI8
226
OP
M-2
NC
I-H92
9
RP
MI8
226
OP
M-2
NC
I-H92
9
U26
6
L363
0
1000
2000
IFN
g (p
g/m
l)
MAGE-A1
HLA-A*02
- + - + +
+ - + + +
+ + + + + + + +
- - - + + + + +
Myeloma Melanoma/Lung
Recognition of tumor cells Rejection of tumors in mice
b a
TRIM
25
SA
MD
9
CO
L28A
1
MM
P27
DA
PK
3
MA
GE
-A1
PM
A/io
no
T2 a
lone
IFN
-γ (p
g/m
l)
Donor 1 Donor 2
Sequence Gene IC50 (nM)
X X X E Y X I K X T1376 motif
K V L E Y V I K V MAGE-A1 4.11
E L L E Y Y I K V TRIM25 23.34
G L L E Y L I K S SAMD9 73.23
K Q F E Y D I K T MMP27 834.74
R S L E Y D I K L COL28A1 4258.75
R L K E Y T I K S DAPK3 5212.32
Potential off-target epitopes
No relevant off-target toxicity
No recognition of: • Allo-MHCs • Primary cells of vital organs
(lung, heart, bone marrow) • Broad panel of self-peptides
-13 -12 -11 -10 -9 -8 -7 -6 -5 -40
50
100
peptide concentration (log M)
IFNγ
(% o
f max
.)Donor 1Donor 2Donor 3
Donor 1Donor 2Donor 3
SAMD9
MAGE-A1
No expression in normal tissue
Safety
à Initiation of Phase I/IIa trial
Antigen expression
MAGE-A1+ HLA-A2+
Commercial Potential
MAGE-A1 TCR / multiple myeloma (US per year, 2016)
New cases 30,330 Deaths 12,650
HLA-A2+ 6325 MAGE-A1+ 822
Costs per treatment 300,000 $ Market penetration 15%
Estimated sales 37 Mio $
Application for many indications!
Ø Cancer Immunotherapy Market (Bio US$, Markets & Markets 2017)
Ø Multiple Myeloma Market (Bio US$, Global Data 2017)
2016 2021
61.9 119.4
2016 2023
12.8 22.6
Preclinic IND Phase I/IIa Discovery
Development Status
NY-ESO (CD4+CD8)
HPV16 E6
Neoantigens (>20)
New HLA variants
A*03:01
A*11:01 C*04:01 B*15:01
B*07:02 C*07:02
MAGE-A1
End of 2017
> 100 antigens
analyzed in vivo
> 500 mice
immunized
> 250 TCRs cloned
> 10 billion T cells
screened
DR1
DR7 DR15
DR3
MHC I MHC II
TCR IP package
Transfer system
Humanized TCR mice
Individual TCRs Groups of TCRs Safety switch
FTO with retroviral vector Patent on Transposon technology
Licence agreement with MDC spin-off
Intellectual Property / Commercialization
What we are looking for 1. VC investment for (pre-) clinical product
development
2. Biotech partner for clinical development of
TCR candidates and sublicensing
3. Fee-for-service TCR isolation
GMP production Validated process Manufacturing licence pending
Complex Know-how No patent filed FTO
Thank you. Max Delbrück Center (MDC)
Thomas Blankenstein Gerald Willimsky Liang-Ping Li Vivian Scheuplein Stephanie Petzold Ioannis Gavvovidis Lucia Poncette Xioajing Chen Dana Hoser Christoph Lampert Arunraj Dahmodaran Meng-Tung Hsu Georgios Papafotiou Wolfgang Uckert Matthias Leisegang
Charité
Antonio Pezzutto Matthias Obenaus Igor Blau Axel Nogai
Holger Specht
GMP facility
Joachim Kopp Martin Vaegler Hana Rauschenbach
Stem Cell Facility, Charité
Charité Research Organization
Medigene AG
Dolores Schendel Carina Wehner Sabine Hauck Christine Leichtle Christiane Eck Silke Raffegerst
S F B – T R 3 6
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