On 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, reported 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) (Free SITC Whitepaper) 2023 November 1-5, 2023, in San Diego, USA (Press release, MediGene, NOV 4, 2023, View Source [SID1234636974]).

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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: View Source

"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.