On September 14, 2024 Medigene AG (Medigene or the "Company", FSE: MDG1, Prime Standard), an oncology platform company focused on the research and development of T cell receptor (TCR)-guided therapies for the treatment of cancer, reported updates for its T cell receptor (TCR) library targeting the Kirsten rat sarcoma viral oncogene homolog (KRAS) and also highlighted advancements of its UniTope and TraCR technology, which serves as a universal system for tagging and tracking recombinant TCRs (rTCRs) across multiple modalities, including T cell receptor engineered T cell (TCR-T) therapies, at the ESMO (Free ESMO Whitepaper) Congress 2024 taking place in Barcelona from September 13-17, 2024 (Press release, MediGene, SEP 14, 2024, https://www.pressetext.com/news/20240914005 [SID1234646624]).
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The presented 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 " will be made available after the conference on Medigene’s website:View Source
"We are excited about our expanding library of mKRAS-specific rTCRs targeting different mutations and HLA allotypes, aiming to broaden treatment options and improve outcomes for patients with difficult-to-treat solid tumors," said Dolores Schendel, CSO at Medigene AG. "Our lead KRAS G12D candidate, enhanced by the costimulatory switch protein (CSP) PD1-41BB, has shown very promising T cell functionality. By overcoming the challenges of the tumor microenvironment that have hindered the effectiveness of TCR-T therapies, we are confident that this program could offer best-in-class efficacy and safety. We are expanding our TCR library and also incorporating new proprietary technologies into our End-to-End (E2E) Platform, including UniTope & TraCR, a universal detection system for any rTCR across various modalities like TCR-T therapies, TCR-guided T cell engagers therapies, and TCR-NK cell therapies. Direct integration of the UniTope tag guarantees 100% co-expression of a unique identifier in a rTCR sequence and provides a significant advancement over current methods for detection of rTCRs in TCR-guided therapeutics. UniTope and TraCR will help us streamline quality control and provide precise data for determining the correct drug dosage for TCR-T therapies."
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
The first data presented showcased recent advancements in the expansion of the Company’s KRAS library, using a high-throughput approach to develop optimal affinity TCRs targeting the mKRAS G12D neoantigen in the context of HLA-A*11 via Medigene’s proprietary E2E Platform. Further in vitro studies characterized the lead TCR candidate in terms of specificity, sensitivity, and safety (3S) while incorporating the PD1-41BB CSP. TCR-expressing T cells, when stimulated by mKRAS G12D-positive tumor cells, showed increased interferon gamma (IFNγ) release. Reduced cancer cell survival was observed 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, with no impact on wild-type KRAS cells. The TCR demonstrated an excellent safety profile, with no off-target toxicity against an extensive panel of healthy cell types. Finally, in vitro data showed that co-expression of PD1-41BB CSP enhanced and sustained T cell function in an rTCR-specific manner, with gated activation that only occurred when the specific peptide-HLA complex was present on target cells, and not through PD-L1 expression alone.
UniTope & TraCR – Universal tagging and tracking system for TCR-T cells integrated directly in the TCR constant region
The second poster displayed the Company´s recently introduced universal TCR tagging and tracking combination technology UniTope & TraCR. Bioinformatic alignment of T cell receptor beta variable sequences enabled a six-amino-acid peptide (UniTope) to be predicted that is not found in natural TCR beta chains and has low immunogenicity. In parallel, an antibody was developed to specifically target this short amino acid peptide (TraCR) and further in vitro experiments demonstrated that TCR-T cells containing the UniTope sequence exhibited similar effects to those of TCR-T cells without the UniTope sequence. Integration of the UniTope sequence in a rTCR guarantees 100% co-expression of the tag and provides a significant advancement over current methods of detection of rTCRs in TCR-guided therapeutics.
In vitro studies confirmed that insertion of UniTope did not alter expression or functionality of rTCRs. In addition, safety assessments confirmed that UniTope-modified rTCRs displayed the same high safety profile as un-modified rTCRs with respect to lack of recognition and killing of 16 healthy cell types.