Medigene presents new data for MDG2011, the first TCR in a novel KRAS library, demonstrating capability of its proprietary E2E Platform to generate multiple enhanced TCR-T therapies against mKRAS G12V A*11
Planegg/Martinsried, November 4, 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, presents novel preclinical data of their MDG2011 program lead candidates which are optimal affinity Kirsten rat sarcoma viral oncogene homologue mutation (mKRAS)-specific T cell receptors (TCRs) targeting human leukocyte antigens (HLA) A*11, in combination with a PD1-41BB costimulatory switch protein (CSP) at the Society for Immunotherapy of Cancer (SITC) 2023 November 1-5, 2023, in San Diego, USA.
The poster with the title “A novel library of optimal affinity KRAS mutation-specific T cell receptors associated with multiple HLAs, in combination with a PD1-41BB armoring and enhancement costimulatory switch receptor” is available on Medigene’s website: https://medigene.com/science/abstracts/
“The unique approach of our End-to-End (E2E) Platform has enabled us to generate three strong lead candidates for our MDG2011 program, of which we have prioritized one, targeting mKRAS G12V-HLA-A*11, confirming our ability to identify optimal affinity TCRs not only for cancer-testis antigens but also for neoantigens, both validated targets for the treatment of solid tumor patients. Our preclinical work revealed fifteen potential TCR candidates specific to mKRAS G12V, from which these three unique TCRs fulfilled and exceeded our criteria of excellent specificity, high sensitivity and safety” said Dr. Selwyn Ho, Chief Executive Officer at Medigene. “Further armoring and enhancing these TCR-T cells with technologies like the PD1-41BB CSP showed that this has clear potential to overcome the immunosuppressive solid tumor microenvironment, leading to improved and sustained outcomes of TCR-T therapies in difficult-to-treat solid tumors.”
Neoantigens (also known as oncogenic driver mutations) are related to mutations that alone are sufficient to initiate and maintain cancer, with the KRAS gene being one of the most frequently altered mutations in solid cancers. To date, 21 so-called missense mutations (in which single amino acids are exchanged) have been identified in the KRAS gene, with G12D, G12V and G12C being the most common. Given the high prevalence of various mutations within the KRAS gene and the limitations of current therapeutic approaches, there is an unmet need to further improve targeted therapies.
The presented data demonstrate, utilizing a high-throughput approach, the generation of optimal affinity TCRs targeting the mKRAS G12V neoantigen presented by multiple HLA-A*11 subtypes through use of the Company’s unique E2E Platform and shows further in vitro characterization with regards to specificity, sensitivity, and safety (3S), of the multiple TCR candidates in combination with the PD1-41BB-CSP.
Robust co-expression of the recombinant TCRs (rTCRs) and the PD1-41BB CSP was demonstrated for the three TCR candidates. The TCRs showed excellent specificity for the mKRAS G12V target, verified by release of interferon-gamma (IFNγ) only detected after stimulation with mKRAS G12V targets but not after stimulation with naturally occurring wild-type KRAS. Each of the three TCR candidates exhibited a unique peptide-specific recognition pattern of G12V peptide presented by different HLA-A*11 subtypes, underpinning the fine specificity of the selected TCR candidates.
All three TCR candidates displayed high sensitivity, responding to very low levels of the mKRAS-G12V peptide presented by antigen-presenting cells pulsed with varying amounts of the mKRAS G12V peptide.
Furthermore, elevated IFNγ release was seen after stimulation of TCR-expressing T cells with tumor cell lines expressing only low levels of mKRAS antigen and cancer cell survival was limited in mKRAS G12V-positive tumor cell lines of different origin following exposure to the T cells co-expressing any of the three rTCR mKRAS G12V-HLA-A*11 with PD1-41BB CSP. These effects were limited to mKRAS G12V-expressing cells, as cancer cells harboring wild-type KRAS were not affected. In addition, increased and sustained killing ability of 3D tumor spheroids was detected with the selected TCR candidates, demonstrating the potent cytotoxic activity directed towards cancer cells with mKRAS G12V.
Finally, the three TCR candidates each showed a favorable safety profile. None of the TCRs recognized HLA allotypes other than HLA-A11 in a panel of cell lines expressing globally common HLA allotypes. Most importantly, healthy cells representing major tissues or organs did not trigger IFNγ release upon exposure to the TCR candidates, approving that cytotoxicity is restricted to cancer cells with no signs of toxicity to healthy tissue.
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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 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 safety, efficacy and durability. 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, differentiated 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 address challenges in developing effective, durable and safe TCR-T therapies. Partnerships with multiple companies including BioNTech and 2seventy bio, continue to validate the platform’s assets and technologies. For more information, please refer to the recent publication by Dolores J. Schendel, published in Frontiers in Oncology, section Molecular and Cellular Oncology: Evolution by Innovation as a Driving Force to Improve TCR-T Therapies.
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.
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.
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