Medigene AG Announces Lead Selection for MDG2021, Expanding TCR-T KRAS Library Targeting Solid Tumors

Medigene AG recently announced it has selected its lead candidate for MDG2021, a T cell receptor engineered T cell (TCR-T) therapy targeting Kirsten rat sarcoma viral oncogene homologue (KRAS) G12D with human leukocyte antigen (HLA)-A*11 being developed in combination with the Company’s PD1-41BB costimulatory switch protein (CSP) technology.

With its proprietary End-to-End (E2E) Platform, the company has successfully generated an optimal KRAS G12D-HLA-A*11 TCR that meets the company’s selection criteria for highly specific, sensitive and safer (3S) TCRs as the lead that will now advance into the pre-clinical stage. The company’s evaluation criteria for TCR selection included sensitive and precise tumor cell recognition combined with simultaneous display of a high safety profile demarked by lack of recognition of panels of healthy cells and tissues, matched and mismatched for HLA.

“We are delighted to announce that we have successfully generated a novel 3S TCR targeting KRAS G12D-A*11 that meets our rigorous selection criteria of high specificity, heightened sensitivity, and promising potential for enhanced safety,” said Dr. Selwyn Ho, Chief Executive Officer at Medigene. “The selection of this KRAS G12D lead-TCR expands our library of TCRs against neoantigens and cancer-testis antigens. Further, with the addition of our armoring & enhancement technology, PD1-41BB CSP to our TCR-T therapies, we are confident that our approach will yield best-in-class TCR-T therapies, providing improved outcomes for patients with to date, difficult-to-treat solid tumors such as colorectal cancer and pancreatic cancer. We are looking forward to presenting initial pre-clinical data on MDG2021 at upcoming scientific conferences in the second half of 2024.”

The company’s E2E Platform continues to generate 3S TCRs with unique and distinctive attributes that will be utilized across multiple therapeutic modalities, including TCR-T therapies, TCR-guided T cell engagers and TCR natural killer cell therapies. The new 3S TCR is designed for co-expression with Medigene’s PD1-41BB CSP to enhance the proliferation, persistence, and cytotoxic function of TCR-T cells, while simultaneously mitigating immunosuppressive effects of the tumor microenvironment.

Following the lead announcement of Medigene’s first KRAS program MDG2011 (KRAS G12V-A*11) in June 2023, MDG2021 is the latest program now in preclinical development within Medigene’s library of neoantigens that comprises multiple KRAS mutations and HLAs. The MDG20xx program is dedicated to further develop the Company’s TCR library, exploring other KRAS neoantigen mutations and HLAs.

Medigene AG (FSE: MDG1) is an immuno-oncology platform company dedicated to developing differentiated T cell therapies to effectively eliminate cancer. Its End-to-End Platform consists of multiple proprietary and exclusive technologies that generate optimal T cell receptors, armor and enhance these T cells to overcome the immunosuppressive tumor microenvironment (TME), and ensure the T cells drug product composition maximizes safety, efficacy and durability of response. This creates potential best-in-class, T cell receptor engineered T cell (TCR-T) therapies to treat multiple solid tumor indications for both its in-house product pipeline and partnering. Medigene’s lead TCR-T program MDG1015 is on track for IND filing in Q3 2024 and CTA filing in Q4 2024. For more information, please visit https://medigene.com/

Medigene’s immunotherapies help activate the patient’s own defense mechanisms by harnessing T cells in the battle against cancer. Medigene’s End-to-End Platform combines multiple exclusive and proprietary technologies to create best-in-class, differentiated TCR-T therapies. The platform includes multiple TCR generation and optimization technologies (eg, Allogeneic-HLA (Allo-HLA) TCR Priming), as well as product enhancement technologies (eg, PD1-41BB and CD40L-CD28 Costimulatory Switch Proteins, iM-TCR) to address challenges in developing effective, durable and safe TCR-T therapies. Partnerships with multiple companies including BioNTech and Regeneron, continue to validate the platform’s assets and technologies.

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, these 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, endometrial 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.