Medigene AG Announces Lead Selection for MDG2011 Representing the First TCR-T Therapy of its KRAS Library
News provided byMedigene AG
Sep 18, 2023, 8:00 AM ET
Planegg/Martinsried, September 18, 2023. Medigene AG (Medigene, the “Company”, FSE: MDG1, Prime Standard), an immuno-oncology platform company focusing on the discovery and development of T cell immunotherapies for solid tumors, announces today that it has selected its lead candidate for MDG2011, a T cell receptor engineered T cell (TCR-T) therapy targeting KRAS (Kirsten rat sarcoma viral oncogene homologue) G12V with HLA-A*11 and being developed in combination with the Company’s PD1-41BB costimulatory switch protein (CSP) technology.
Medigene’s end-to-end (E2E) platform, has successfully generated not one but three KRAS G12V-HLA-A*11 TCRs, each with distinct, multiple HLA-A*11 subtype recognition patterns that exceed the Company’s selection criteria for highly specific, sensitive and potentially safer (3S) TCRs. After deploying Medigene’s proprietary algorithms for evaluation of the unique characteristics of each of the 3S TCRs, including peptide specificity, tumor cell recognition and off-target toxicity, the Company has prioritized one of the 3S TCRs as the lead to move forward to the pre-clinical stage for Medigene’s MDG2011 program.
“The unique approach of our E2E platform to generate and optimize 3S TCRs, has continued to deliver above expectations and we are delighted to have been presented with the positive challenge of having to select a lead from three strong candidates for our MDG2011 program targeting KRAS G12V-A11,” said Dr. Selwyn Ho, Chief Executive Officer at Medigene.
“The selection of this first mKRAS (mutant KRAS) lead TCR further validates our capabilities to generate 3S TCRs across both neoantigens and cancer-testis antigens. By combining all our TCRs with our PD1-41BB or CD40L-CD28 costimulatory switch proteins, we remain convinced that our approach will consistently deliver best-in-class TCR-T therapies leading to improved outcomes for patients suffering from difficult-to-treat solid tumors. We look forward to presenting the first pre-clinical data on MDG2011 at upcoming scientific conferences in the last quarter of 2023.”
The Company’s E2E platform continues to generate 3S TCRs with unique attributes that add additional dimensions to the potential of Medigene’s TCR-T therapies as well as to confirm the Company’s discovery research efforts. One such attribute is the identification of a TCR candidate demonstrating bi-specific recognition for both the KRAS G12V and G12C mutations. Directed TCR discovery efforts in the future will enable identification of an optimal KRAS G12C-specific TCR lead. The two remaining KRAS G12V-A11 TCRs not selected for the MDG2011 program will be added to Medigene’s KRAS TCR library for potential future programs that align the product vision with the profile of each TCR. Patents have been filed for each of the three TCRs.
MDG2011 is the first program of Medigene’s pipeline expansion into a library of neoantigens (also known as oncogenic driver mutations) that comprise multiple KRAS mutations and HLAs (human leukocyte antigens) including, but not limited to:
- KRAS G12V-HLA-A*11 (MDG2011)
- KRAS G12V-HLA-A*03 (MDG2012)
- KRAS G12D-HLA-A*11 (MDG2021)
These TCRs will be combined with the PD1-41BB and/or the CD40L-CD28 costimulatory switch proteins to enhance penetration, proliferation, persistence and enhanced cytotoxic function of Medigene’s TCR-T cells while mitigating the immunosuppressive effects of the tumor microenvironment.
Neoantigens are tumor-specific antigens, which play a critical role in the growth and maintenance of tumors. These mutations are found in many solid tumors and their prevalence varies depending on the cancer type. Importantly, if present, these mutations are found in each tumor cell. KRAS mutations are widely recognized as the most common oncogene mutations in difficult to treat solid tumors existing in ~30% of solid tumors, such as pancreatic, colorectal, endometrial and non-small-cell lung cancer. Global incidence of solid tumors expressing KRAS mutations is estimated to be in excess of 300,000 patients.
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About Medigene AG
Medigene AG (FSE: MDG1) is an immuno-oncology platform company dedicated to developing T cell therapies to effectively eliminate cancer. Its end-to-end technology platform, built on multiple proprietary and exclusive TCR generation and optimization, as well as product enhancement technologies, allows Medigene to create best-in-class differentiated, T cell receptor engineered T cell (TCR-T) therapies for multiple solid tumor indications that are optimized for both safety and efficacy. This platform provides product candidates for both its in-house therapeutics pipeline and partnering. For more information, please visit www.medigene.com
About Medigene’s End-to-End Platform
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 TCR-T therapies. The platform includes multiple TCR generation and optimization technologies (e.g., Allogeneic-HLA (Allo-HLA) TCR Priming), as well as product enhancement technologies (e.g., PD1-41BB and CD40L-CD28 Costimulatory Switch Proteins, Precision Pairing) to aid the development of differentiated TCR-T therapies. Partnerships with multiple companies including BioNTech, 2seventy bio, and Hongsheng Sciences, continue to validate the platform’s assets & technologies.
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, 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.
About Medigene’s CD40L-CD28 Costimulatory Switch Protein
The CD40L/CD40 pathway plays a major role in immune regulation and homeostasis. The CD40L (ligand) is a member of the tumor necrosis family and primarily expressed on activated T cells:
- CD4+ T cells, where its primary function is in the T cell-mediated activation of dendritic cells (DCs) and monocytes.
- CD8+ T cells thus promoting their expansion and differentiation through DCs.
CD40 is also present on B cells and expressed on dendritic cells (DCs), monocytes and macrophages as well as by non-hematopoietic cells such as epithelial and endothelial cells.
Expression of CD40 has been confirmed in a wide variety of solid tumors like melanoma, prostate, and lung cancers, as well as in carcinomas of the nasopharynx, bladder, cervix, and ovary.
CD28 is expressed on T cells providing costimulatory signals required for T cell activation and survival.
Thus, the CD40L/CD40 pathway plays a crucial role in activation of T cells.
Medigene´s CD40L-CD28 costimulatory switch protein may contribute to an enhancement of cellular immune responses in several ways:
- CD40L expressed on activated T cells and CD40 expressed on DC transmits a signal to the antigen presenting cells that results in upregulation of costimulatory molecules and further stimulation of optimal T cell responses.
- CD40-expressing tumor cells can be subject to apoptosis by direct interaction with CD40L-CD28-engineered T cells independent of MHC/peptide-specific targeting.
- CD40 is found in the TME of the tumor endothelium, where engagement with CD40L-CD28-engineered T cells enables upregulation of adhesion molecules, thereby improving T cell infiltration into tumors.
Thus, the CD40L-CD28 costimulatory switch protein acts via DCs and other non-tumor cells and may provide complementary effects to other switch receptors that exert their effects mainly via PD-1 expressing T cells.
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.
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.
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