Planegg/Martinsried – Medigene AG (Medigene, FSE: MDG1, Prime Standard), a clinical stage immuno-oncology company focusing on the development of T cell immunotherapies, today presents promising pre-clinical data on its lead PRAME-specific, HLA-A2-restricted T cell receptor (TCR) candidate “TCR-4” for future T cell receptor-modified T cell (TCR-T) therapy against solid tumors at the American Association for Cancer Research Virtual Annual Meeting (AACR) 2021. The poster can be found on Medigene’s website: https://medigene.com/technologies/abstracts
TCR-4 – high natural in vitro and in vivo anti-tumor reactivity and specificity
TCR-4 is a non-mutated TCR isolated from a healthy donor that, in the context of HLA-A2, specifically recognizes a peptide stemming from the PRAME protein, an antigen of the cancer-testis-antigen family. In cell culture experiments no cross-recognition of peptides on other HLA-types or off-target recognition of critical healthy tissues was observed. Also, there was no off-target toxicity towards slightly modified peptides, which were expressed and presented by target cells. In a skin cancer mouse model, all mice treated with TCR-Ts expressing TCR-4 survived the observation period of 67 days and the cancer was well controlled. Addition of the PD1-41BB switch receptor improved the TCR-T cells’ effector function in a challenging in vitro environment with repeated exposure to tumor cells mimicking the real-life situation in solid cancers.
Prof. Dolores Schendel, Chief Executive Officer and Chief Scientific Officer at Medigene: “TCR-4 is another successful lead candidate from our high-throughput TCR generation process. It shows high natural affinity for the PRAME target demonstrated by potent preclinical in vitro and in vivo efficacy. Combining this TCR with our PD1-41BB switch receptor should result in a very promising TCR-T product, especially for the treatment of solid tumors. We are looking forward to present further in vivo data of TCR-4 in combination with the PD1-41BB switch receptor in the near future.”
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Medigene AG (FSE: MDG1, Prime Standard, ISIN DE000A1X3W00) is a publicly listed biotechnology company headquartered in Martinsried near Munich, Germany. The company is developing highly innovative immunotherapies to target various forms and stages of cancer. Medigene concentrates on the development of personalized T cell-based therapies, with associated projects currently in pre-clinical and clinical development.
For more information, please visit medigene.com
About Medigene’s TCR-Ts
TCR-T technology arms a patient’s own T cells with tumor-specific T cell receptors. The T cell receptor-modified T cells (TCR-T cells) are then able to detect and efficiently kill tumor cells. This immunotherapy approach attempts to overcome the patient’s tolerance towards cancer cells and tumor-induced immunosuppression by activating and modifying the patient’s T cells outside the body (ex vivo).
Medigene is conducting a Phase I/II clinical trial of its TCR-T candidate MDG1011 in the blood cancer indications AML and MDS. In addition, Medigene is establishing a pipeline of TCRs and has collaborations with bluebird bio, Inc. and Cytovant Sciences HK Ltd. addressing solid tumor indications.
About Medigene’s PD1-41BB switch receptor
Checkpoint inhibition via PD1-PDL1 pathway: Solid tumor cells are known to be sensitive to killing by activated T cells. Tumor cells can escape this killing activity by expressing inhibitory molecules, so-called ‘checkpoint proteins’, such as 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 by tumors represents an adaptive immune resistance mechanism that can lead to tumor survival and growth.
The 4-1BB co-stimulatory signaling pathway: Effective T cell immune responses to antigens typically require costimulatory signals to be received alongside the primary antigenic stimulation via the T cell receptor (TCR). The intracellular signaling domains of the 4-1BB protein offer a well-characterized pathway to positively enhance T cell responses.
Medigene’s PD1-41BB switch receptor takes advantage of the binding of PD-1 on the T cells to PD-L1 on tumors. In the switch receptor, the inhibitory signaling domain of PD-1 has been substituted with the activating signaling domain of 4-1BB. As a result, the switch receptor then delivers an activating signal to the TCR-T cells (not the usual inhibitory signal of PD-1). This enables the PD1-41BB-modified TCR-T cells to proliferate strongly in the presence of PD-L1-positive tumor cells and to mediate greater killing of tumor cells upon repeated exposure. Additionally, signals mediated through the switch receptor also enhance metabolic fitness of TCR-T cells, enabling better function in conditions of low levels of glucose or high levels of the immunosuppressive factor TGFß, two conditions that are characteristic of strongly hostile tumor microenvironments.
PRAME (PReferentially expressed Antigen in MElanoma) is a tumor antigen of the cancer-testis-antigen family which is over-expressed in various solid tumors such as lung, ovarian, uterine and skin cancers. Expression in healthy tissue is limited to the testis, which itself is an immuno-privileged tissue that usually cannot be attacked by the body’s own immune cells. This makes PRAME very suitable as a target antigen for TCR-T therapies.
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.
Dr. Gary Waanders, Dr. Anna Niedl
Phone: +49 89 2000 3333 01
Phone: +44 7483 284 853