Medigene AG: Medigene Presents Superior TCR-T Cell Functionality by Inclusion of a Costimulatory Switch Protein

Planegg/Martinsried (pta008/02.05.2024/08:30 UTC+2)

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, presented superior T cell receptor engineered T (TCR-T) cell functionality upon combination of optimal affinity 3S (sensitive, specific and safe) TCRs with the PD1-41BB costimulatory switch protein (CSP) at the 7th International Neoantigen Summit held in Amsterdam, Netherlands from April 29 - May 1, 2024.

The presentation with the title "KRAS Mutation-Specific TCR-T Cells are Empowered for Improved Multi-Functionality & Durability by Inclusion of a Costimulatory Switch Protein" is available on Medigene's website: https://medigene.com/science/abstracts/

Overcoming the immunosuppressive solid tumor microenvironment (TME) stands as a major hurdle for durable TCR-T therapies in patients. The PD-1/PD-L1 axis suppresses T cell activation, proliferation, survival, cytokine secretion and cytotoxicity in a TME with tumor cells that express PD-L1. The Company´s PD1-41BB CSP effectively counters this tumor self-defense mechanism against T cell attack by replacing the inhibitory signaling domain of PD-1 expressed by TCR-T cells with the activating signaling domain of 4-1BB, thereby improving TCR-T cell functionality.

"Our PD1-41BB CSP, a proprietary component of our End-to-End (E2E) Platform, provides an innovative technology that can be paired with diverse optimal affinity 3S-TCRs that target cancer-testis antigens or neoantigens generated using our high-throughput TCR discovery process," said Dr. Selwyn Ho, Chief Executive Officer at Medigene. "Extensive in vitro assessments underscore the significant advantages of armoring and enhancing 3S-TCRs with our PD1-41BB CSP, showcasing the potential to surmount the immunosuppressive TME of solid tumors. This breakthrough combination promises enhanced and persistent efficacy of TCR-T therapies in difficult-to-treat solid tumors. The PD1-41BB CSP can be used not only to improve TCR-T therapies but also holds potential to improve functions in other cell types as well as for application in chimeric antigen receptor T cell therapies."
"Notably, our innovative TCR discovery method allowed us to identify TCRs possessing distinctive supplementary qualities, demonstrating functionality even in absence of the CD8 co-receptor, normally an important component of immune defense."

The data presented displayed the exceptional specificity and sensitivity of TCR-T cells co-expressing the PD1-41BB CSP with three different 3S-TCRs that recognize the mKRAS (mutant Kirsten rat sarcoma viral oncogene homologue) G12V neoantigen. This was seen by elevated interferon gamma (IFNγ) secretion, which was solely observed following TCR-T cell stimulation with mKRAS G12V-positive tumor cells but not by stimulation with any tumor or healthy cell type expressing naturally occurring wild-type KRAS protein. Each of the three 3S TCRs displayed exceptionally high sensitivity for the mKRAS G12V neoantigen, as evidenced by their response to activation by exceedingly low levels of mKRAS-G12V peptide. Coexpression of the PD1-41BB CSP strongly enhanced TCR-T cell functionality and allowed sustained cytotoxicity to be directed against 3D tumor spheroids through multiple rounds of tumor exposure, underscoring the potent anti-cancer activity of the TCR-T cells.

Finally, all three 3S TCRs exhibited excellent safety profiles. TCR-T cells expressing each of the 3S TCRs, in combination with the PD1-41BB CSP, were not activated to secrete IFNγ nor to mediate killing upon exposure to healthy cells from major tissues or organs, confirming their selective cytotoxicity towards cancer cells without toxicity for healthy tissue.

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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 expected to receive IND/CTA approval in the second half of 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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Emitter:	Medigene AG Lochhamer Straße 11 82152 Planegg/Martinsried Germany
Contact Person:	Medigene PR/IR
Phone:	+49 89 2000 3333 01
E-Mail:	investor@medigene.com
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