Planegg/Martinsried, May 15, 2024.
Medigene AG (Medigene or the “Company”, FSE: MDG1, Prime Standard),
an immuno-oncology platform company focusing on the discovery and
development of T cell immunotherapies for solid tumors, today
presents the company’s proprietary T cell receptor (TCR) discovery
process to obtain optimal affinity 3S (sensitive, specific and
safe) TCRs at the 21th Association for Cancer Immunotherapy (CIMT)
Annual Meeting in Mainz from May 15 - 17, 2024. Data presented also
shows the clear benefit of adding the PD1-41BB costimulatory switch
protein (CSP) to further armor and enhance these 3S TCR-T cells,
which enables them to overcome the immunosuppressive tumor
microenvironment.
The poster with the title “Selection of superior
KRAS G12V mutation-specific T cell receptors with unique
characteristics for 3rd generation armored and enhanced T cell
therapy” will be available on Wednesday, May 15, 2024, following
the presentation on Medigene’s website:
https://medigene.com/science/abstracts/
“The discovery process of unique TCR sequences
is the first key step to generate TCR-T cells with optimal safety,
efficacy and durability,” said Dr. Selwyn Ho, Chief Executive
Officer at Medigene. “Employing a high-throughput process as part
of our End-To-End (E2E) Platform enabled us to discover unique TCR
sequences with distinct features with respect to specificity,
sensitivity and safety (3S). These potential best-in-class 3S TCRs
hold promise for utilization across diverse modalities, here
focusing on T cell receptor engineered T cell (TCR-T) therapies,
but also for use in T cell engagers and TCR natural killer cell
therapies. “
He continued: “Our TCRs can undergo further
enhancement through integration of various technologies within our
E2E Platform such as with our exclusive PD1-41BB CSP, which
significantly enhances TCR-T cell functionality, persistence and
proliferation and offers the promise of highly effective and
durable TCR-T therapies in patients.”
The presented data highlighted the specificity
and sensitivity of TCR-T cells co-expressing the PD1-41BB CSP
alongside one of three distinct 3S TCRs targeting the mKRAS G12V
neoantigen. These TCR-T cells displayed markedly increased
secretion of interferon gamma (IFNγ) observed upon TCR-T cell
stimulation with mKRAS G12V-positive tumor cells, contrasting with
the absence of IFN γ secretion upon stimulation with any tumor or
healthy cell expressing naturally occurring wild-type KRAS
protein.
All three 3S TCRs also demonstrated high
sensitivity to the mKRAS G12V neoantigen, as demonstrated by their
activation in response to extremely low levels of mKRAS-G12V
peptide. Concurrent expression of the PD1-41BB CSP significantly
augmented TCR-T cell functionality, enabling sustained cytotoxicity
targeting 3D tumor spheroids across multiple rounds of tumor
exposure. This underscores the potent anti-cancer efficacy of the
TCR-T cells.
From a safety perspective, all three 3S TCRs
combined with the PD1-41BB CSP demonstrated favorable safety
profiles, with no IFNγ secretion or cytotoxicity when exposed to
healthy cells from major tissues or organs, affirming their
selective cytotoxicity towards cancer cells while sparing healthy
tissue from toxicity.
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About Medigene AG
Medigene AG (FSE: MDG1) is an immuno-oncology
platform company dedicated to developing differentiated T cell
therapies for treatment of solid tumors. Its End-to-End Platform is
built on multiple proprietary and exclusive technologies that
enable the Company to generate optimal T cell receptors against
both cancer testis antigens and neoantigens, armor and enhance
these T cell receptors engineered (TCR) -T cells to create
best-in-class, differentiated TCR-T therapies, and optimize the
drug product composition for safety, efficacy and durability. The
End-to-End Platform provides product candidates for both its own
therapeutics pipeline and partnering. Medigene’s lead TCR-T program
MDG1015 is on track for IND filing in 3Q 2024 and CTA filing in 4Q
2024. For more information, please visit https://medigene.com/
About Medigene’s TCR-T Cells
T cells are at the center of Medigene’s
therapeutic approaches. Medigene’s immunotherapies help activate
the patient’s own defense mechanisms, and harness T cells in the
battle against cancer. Medigene’s therapies arm the patient’s own T
cells with tumor-specific T cell receptors (TCRs) creating
TCR-modified T cells with enhanced potential to detect and
efficiently kill cancer cells.Medigene’s approach to immunotherapy
is designed to overcome the patient’s tolerance of cancer cells and
tumor-induced immunosuppression. By activating the patient’s T
cells outside the body, genetically modifying them with
tumor-specific TCRs and expanding the resultant activated TCR-T
cells, patients can rapidly be given large numbers of
tumor-specific T cells to fight their cancer.
About Medigene’s PD1-41BB Costimulatory
Switch Protein
Checkpoint inhibition via PD-1/PD-L1
pathway:
Cells of solid tumors are sensitive to killing
by activated T cells but can escape this killing activity by
producing inhibitory molecules known as ‘checkpoint proteins’, such
as the Programmed Death Ligand 1 (PD-L1), on their surface. When
this occurs, activated T cells which express PD-1, the natural
receptor for PD-L1, are inactivated. The expression of PD-L1 is an
adaptive immune resistance mechanism for tumors that can help them
survive and grow.
The 4-1BB (CD137) costimulatory signaling
pathway:
Effective T cell immune responses to antigens
typically require both a primary antigenic stimulation via the T
cell receptor (TCR) and costimulatory signals. The intracellular
signaling domains of the 4-1BB protein offer a well-characterized
pathway to costimulation and enhanced T cell responses.
Medigene’s PD1-41BB switch receptor turns the
tumor’s attempted self-defense mechanism against the tumor by
substituting the inhibitory signaling domain of PD-1 with the
activating signaling domain of 4-1BB. Therefore, instead of
inactivating T cells, the switch receptor delivers an activating
signal to TCR-T cells. PD1-41BB-modified TCR-T cells proliferate
strongly in the presence of PD-L1-positive tumor cells and kill
more tumor cells upon repeated exposure. Additionally, switch
receptor signals enable TCR-T cells to function better with low
levels of glucose or high levels of TGFß, two conditions
characteristic of strongly hostile tumor microenvironments.
About KRAS
KRAS (Kirsten rat sarcoma viral oncogene
homologue) belongs to the group of small so-called
Guanosine-5′-triphosphate (GTP)-binding proteins, known as RAS-like
GTPases. Under physiological conditions KRAS tightly regulates cell
proliferation and survival.In cancer, KRAS is found frequently
altered, in a wide variety of often fatal solid cancer types like
pancreatic ductal adenocarcinoma, non-small-cell lung cancer, and
colorectal cancer. Mutations in the KRAS gene result in the
creation of neoantigens which drive uncontrolled proliferation of
cancer cells. These mutations within the KRAS gene are unique to
cancer cells and absent in healthy normal tissue, making KRAS an
attractive target for TCR-T therapies. T cell receptor engineered T
cell therapies offer a promising approach to targeting these
mutations and addressing the challenges posed by solid tumors.
Unlike CAR-T cells, which require surface antigens for recognition
and may have limitations in target accessibility, TCR-T cells
recognize a broader range of targets including intracellular
proteins like neoantigens. This unique ability makes TCR-T
therapies particularly well-suited for targeting KRAS mutations and
other challenging neoantigens.
This press release contains forward-looking
statements representing the opinion of Medigene as of the date of
this release. The actual results achieved by Medigene may differ
significantly from the forward-looking statements made herein.
Medigene is not bound to update any of these forward-looking
statements. Medigene® is a registered trademark of Medigene AG.
This trademark may be owned or licensed in select locations
only.
Medigene AG
Pamela Keck Phone: +49 89 2000 3333 01 E-mail:
investor@medigene.com
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