Medigene Updates KRAS Library and UniTope & TraCR Tech at ESMO 2024

Planegg/Martinsried, September 14, 2024. Medigene AG (Medigene or the “Company”, FSE: MDG1, Prime Standard), an oncology platform company specializing in T cell receptor (TCR)-guided therapies for cancer treatment, showcased updates to its TCR library targeting the Kirsten rat sarcoma viral oncogene homolog (KRAS) and advancements in its UniTope and TraCR technology during the ESMO Congress 2024 in Barcelona from September 13-17, 2024.

The presentation included two posters: “Advancing a multi-dimension KRAS mutation-specific T cell receptor (TCR) library with a 3S TCR targeting the G12D mutation to address large global patient populations” and “UniTope & TraCR - Universal tagging and tracking system for TCR-T cells integrated directly in the TCR constant region.” These will be available on the Company’s website post-conference.

Dolores Schendel, CSO at Medigene AG, expressed enthusiasm about the expanding library of mKRAS-specific rTCRs targeting various mutations and HLA allotypes, aiming to enhance treatment options for challenging solid tumors. The lead KRAS G12D candidate, augmented by the costimulatory switch protein (CSP) PD1-41BB, has demonstrated promising T cell functionality. Schendel emphasized the potential of this program to overcome tumor microenvironment challenges that have historically impeded TCR-T therapies, potentially offering superior efficacy and safety. The Company is incorporating new proprietary technologies such as UniTope & TraCR into its End-to-End (E2E) Platform, a universal detection system for rTCRs across various modalities including TCR-T therapies, TCR-guided T cell engagers, and TCR-NK cell therapies. The direct integration of the UniTope tag ensures complete co-expression of a unique identifier in an rTCR sequence, providing a major advancement in the detection methods of rTCRs in TCR-guided therapeutics. UniTope and TraCR streamline quality control and provide precise data for accurate drug dosing in TCR-T therapies.

The first poster detailed advancements in Medigene's KRAS library, developed through a high-throughput approach to create optimal affinity TCRs targeting the mKRAS G12D neoantigen within the context of HLA-A*11 utilizing Medigene’s proprietary E2E Platform. Further in vitro studies characterized the lead TCR candidate's specificity, sensitivity, and safety (3S) while incorporating the PD1-41BB CSP. T cells expressing this TCR, when stimulated by mKRAS G12D-positive tumor cells, exhibited increased interferon gamma (IFNγ) release. The cancer cell survival rate decreased when mKRAS G12D-positive tumor cell lines from various origins were exposed to T cells co-expressing the rTCR mKRAS G12D-HLA-A*11 and PD1-41BB CSP. These effects were specific to mKRAS G12D, showing no impact on wild-type KRAS cells. The TCR exhibited an excellent safety profile, with no off-target toxicity against a broad panel of healthy cell types. Additionally, in vitro data confirmed that PD1-41BB CSP co-expression enhanced and sustained T cell function in an rTCR-specific manner, with activation gated to occur only when the specific peptide-HLA complex was present on target cells.

The second poster introduced the Company’s universal TCR tagging and tracking technology, UniTope & TraCR. Bioinformatic alignment of T cell receptor beta variable sequences predicted a six-amino-acid peptide (UniTope) not found in natural TCR beta chains and with low immunogenicity. An antibody (TraCR) was developed to target this short amino acid peptide, and further in vitro experiments showed that TCR-T cells containing the UniTope sequence exhibited effects similar to those without the sequence. Integration of the UniTope sequence in a rTCR ensures 100% co-expression of the tag, representing a significant breakthrough over current rTCR detection methods. In vitro studies confirmed that the insertion of UniTope did not alter rTCR expression or functionality, and safety assessments confirmed that UniTope-modified rTCRs had the same high safety profile as unmodified rTCRs, with no recognition or killing of 16 healthy cell types.