Medigene publication details augmentation of PRAME-specific TCR-4 by PD1-41BB switch receptor

Planegg/Martinsried (25.04.2022) - Medigene AG (http://www.medigene.com) (Medigene, FSE: MDG1, Prime Standard), an immuno-oncology company focusing on the development of T-cell-based cancer therapies, announces the publication of a new peer-reviewed publication in the journal Cancers showing that the chimeric PD1-41BB receptor augments antigen-specific activity of T cell receptor-modified T cells (TCR-T cells) while retaining a favorable safety profile. The data suggests that the PD1-41BB switch receptor is a promising tool to overcome PD-1/PD-L1 inhibition in the tumor microenvironment of solid cancer without the negative side-effects associated with the use of systemic PD-1/PD-L1 checkpoint inhibitor antibodies.

The inhibitory PD-1/PD-L1 checkpoint axis is a negative influence on T cell efficacy, fitness and persistence. Systemic use of anti-checkpoint antibodies benefits clinical outcomes in some patients but is often associated with drug-related immunotoxicities. Medigene developed the PD1-41BB chimeric receptor, which is exclusively expressed in the therapeutically active TCR-T cells to switch inhibitory PD-1/PD-L1 interactions into positive signals that enhance antigen-specific TCR-T cell function.

The publication describes how Medigene isolated the HLA-A2-restricted, PRAME-specific T cell receptor (TCR) "TCR-4" from blood from healthy donors (tapping a non-tolerized T cell repertoire) and how TCR-T cells expressing TCR-4 and the PD1-41BB switch receptor show improved effector functions, a favorable safety profile in vitro, reject tumors in vivo and have a poly-cytokine profile upon antigen-specific activation.

Prof. Dolores Schendel, Chief Executive Officer and Chief Scientific Officer of Medigene: "We are proud of the high quality of this TCR that we identified and subsequently characterized using our proprietary high-throughput TCR screening technology. Also, after more than 40 years in T cell research, I am deeply impressed by how much our PD1-41BB switch receptor enhances the functional properties of TCR-T cells. BioNTech has also recognized the potential in our technologies and purchased the "TCR-4" program as well as received licenses to the PD1-41BB switch receptor. We believe that these and other approaches which we are developing will be the key to obtaining greater efficacy in TCR-T immunotherapies against solid cancers."

The Cancers publication is titled "T-Cells Expressing a Highly Potent PRAME-Specific T-Cell Receptor in Combination with a Chimeric PD1-41BB Co-Stimulatory Receptor Show a Favorable Preclinical Safety Profile and Strong Anti-Tumor Reactivity" and has recently been published online: https://www.mdpi.com/2072-6694/14/8/1998

About Medigene

Medigene AG (FSE: MDG1, ISIN DE000A1X3W00, Prime Standard) is a publicly listed biotechnology company headquartered in Planegg/Martinsried near Munich, Germany. With its scientific expertise, Medigene is working on the development of innovative immunotherapies to enhance T cell activity against solid cancers in fields of high unmet medical need.

Medigene's strategy is to develop its own therapies towards clinical proof-of-concept. In addition, the Company offers selected partners the opportunity to discover and develop therapies on the basis of its proprietary technology platforms. In return for such partnerships, Medigene expects to receive upfront and milestone payments as well as research and development funding and royalties on future product sales.

For more information, please visit https://www.medigene.com

About Medigene's TCR-Ts

T cells are at the center of Medigene's therapeutic approaches. With the aid of Medigene's immunotherapies the patient's own defense mechanisms are activated, and T cells harnessed in the battle against cancer. Medigene's therapies arm the patient's own T cells with tumor-specific T cell receptors (TCRs). The resulting TCR-Ts should thereby be able to detect and efficiently kill cancer cells.

This approach to immunotherapy aims to overcome the patient's tolerance to cancer cells and tumor-induced immunosuppression by activating the patient's T cells outside the body, genetically modifying them with tumor-specific TCRs and finally multiplying them. In this way, large numbers of specific T cells are made available to patients to fight the cancer within a short period of time.

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.

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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