Medigene Presents Preclinical Data on Optimal Affinity TCRs Targeting the Neoantigen Mutant KRAS

Medigene AG recently presented 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 is available 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. 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.

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.

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.

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.

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/