Medigene AG: Medigene's PD1-41BB switch receptor improves TCR-T cell functionality against solid tumors

ePoster presentation at the ESMO Congress, 16-21 September 2021

Planegg/Martinsried (pta008/16.09.2021/08:30 UTC+2) Medigene AG (Medigene, FSE: MDG1, Prime Standard), a clinical stage immuno-oncology company focusing on the development of T cell immunotherapies, presents compelling new pre-clinical data on the cellular functionality of its lead T cell receptor-modified T cell therapy (TCR-T) candidate containing the PRAME-specific T cell receptor (TCR) "TCR-4" combined with Medigene's PD1-41BB switch receptor.

[i]In vitro[/i] and [i]in vivo[/i], the co-expression of the PD1-41BB switch receptor and TCR-4 on TCR-T cells led to an enhanced response to antigen. [i]In vitro[/i], co-expression enhanced TCR-T proliferation as well as tumor cell killing and increased the release of cytokine messengers, particularly of effector, stimulatory and chemo-attractive cytokines. In an [i]in vivo[/i] model, expression of PD1-41BB together with TCR-4 showed the same effects as during the [i]in vitro[/i] experiments and promoted tumor clearance substantially. Importantly, co-expression of TCR-4 and the PD1-41BB switch receptor did not impede the favorable preclinical safety profile.

The ePoster 1007P is entitled "T cells transgenic for a highly potent PRAME-specific TCR and a chimeric PD1-41BB co-stimulatory receptor represent a promising approach for the treatment of solid tumors." It will be presented as part of the European Society for Medical Oncology (ESMO) Congress being held virtually on 16-21 September 2021. The poster can be found on Medigene's website: https://www.medigene.com/technologies/abstracts

Prof. Dolores Schendel, Chief Executive Officer and Chief Scientific Officer at Medigene: "The PD1-41BB switch receptor clearly improves TCR-T performance. With PD1-41BB, TCR-4 T cells showed a higher percentage of poly-functional T cells than without. With the PD1-41BB switch receptor co-expressed, a higher proportion of single cells secreted 4-10 cytokines simultaneously. Furthermore, with PD1-41BB co-expression we saw a high number of effector and stimulatory cytokines, and raised levels of chemo-attractive cytokines, which help T cells to migrate towards their target tissue in the body. These data underline our decision to advance the development of the PD1-41BB switch receptor in tandem with TCR-4 in PRAME-positive solid tumors."

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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 pipeline includes preclinical as well as clinical programs in development.

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.

About PRAME

PRAME (PReferentially expressed Antigen in MElanoma) is a tumor antigen of the cancer-testis-antigen family which is over-expressed in various solid tumors. 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.

[i]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.[/i]

Medigene
Dr. Anna Niedl
Phone: +49 89 2000 3333 01
E-mail: investor@medigene.com
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Emitter:	Medigene AG Lochhamer Straße 11 82152 Planegg/Martinsried Germany
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Phone:	+49 89 2000 3333 01
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