CD40L-CD28 costimulatory switch receptor

	Status	2023-05-02 use/installation existent
	Organisation	Medigene AG (FSE: MDG1, Prime Standard)
	Group	Medigene (Group)
	Original research	Helmholtz-Zentrum München – Deutsches Forschungszentrum für Gesundheit und Umwelt (GmbH) (HMGU)

Medigene AG. (5/2/23). "Press Release: Medigene Acquires Worldwide, Exclusive License of CD40L-CD28 Costimulatory Switch Receptor". Planegg.

> Medigene accelerates the expansion of its end-to-end platform of multiple, combinable, exclusive and proprietary technologies with the potential to create best-in-class T cell receptor engineered T cell (TCR-T) therapies for patients with solid tumors

> CD40L-CD28 costimulatory switch receptor engages the broader immune system by interacting with and activating non-tumor cell types residing in the immunosuppressive tumor microenvironment (TME)

> CD40L-CD28 costimulatory switch receptor provides the potential to break down tumor stroma components allowing better infiltration of engineered T cells into the tumor with greater access to tumor cells

Medigene AG (Medigene, FSE: MDG1, Prime Standard), an immuno-oncology platform company focusing on the discovery and development of T cell immunotherapies for solid tumors, today reports it has partnered with Helmholtz Munich to acquire the exclusive, worldwide rights to the CD40L-CD28 costimulatory switch receptor adding to the portfolio of technologies within Medigene’s end-to-end platform.

“The CD40L-CD28 costimulatory switch receptor expands our suite of “Product Enhancement” technologies within our platform and joins our existing PD1-41BB costimulatory switch receptor as a technology that has the potential to further enhance the anti-tumor activity of our TCR-T cells and improve their ability to overcome the immunosuppressive solid tumor microenvironment.” said Prof. Dolores Schendel, Chief Scientific Officer.

“We believe that the beneficial effects of the CD40L-CD28 costimulatory switch receptor may be separate or even complementary to those of our existing technologies. We look forward to generating and sharing the data for this in due course.”

— end of press release —

About Medigene AG

Medigene AG (FSE: MDG1) is an immuno-oncology platform company dedicated to developing T cell therapies to effectively eliminate cancer. Its end-to-end technology platform, built on multiple proprietary and exclusive product development and product enhancement technologies, allows Medigene to create best-in-class differentiated, T cell receptor engineered T cell (TCR-T) therapies for multiple solid tumor indications that are optimized for both safety and efficacy. This platform provides product candidates for both its in-house therapeutics pipeline and partnering. For more information, please visit www.medigene.com

About Medigene’s End-To-End Platform

Medigene’s immunotherapies help activate the patient’s own defense mechanisms by harnessing T cells in the battle against cancer. Medigene’s end-to-end platform combines multiple exclusive and proprietary technologies to create best-in-class TCR-T therapies. The end-to-end platform includes multiple product development optimization technologies (e.g. Allogeneic-HLA (Allo-HLA) TCR Priming) and enhancement technologies, (e.g. PD1-41BB Switch Receptor, Precision Pairing) to aid the development of differentiated TCR-T therapies. Partnerships with multiple companies including BioNTech, 2seventy bio, and Hongsheng Sciences, continue to validate the platform’s assets & technologies.

About CD40L-CD28 Costimulatory Switch Receptor

The CD40L/CD40 pathway plays a major role in immune regulation and homeostasis. The CD40L (ligand) is a member of the tumor necrosis family and primarily expressed on activated T cells:

> CD4+ T cells, where its primary function is in the T cell-mediated activation of dendritic cells (DCs) and monocytes.

> CD8+ T cells thus promoting their expansion and differentiation through DCs.

CD40 is also present on B cells and expressed on dendritic cells (DCs), monocytes and macrophages as well as by non-hematopoietic cells such as epithelial and endothelial cells.

Expression of CD40 has been confirmed in a wide variety of solid tumors like melanoma, prostate, and lung cancers, as well as in carcinomas of the nasopharynx, bladder, cervix, and ovary.

CD28 is expressed on T cells providing costimulatory signals required for T cell activation and survival. Thus, the CD40L/CD40 pathway plays a crucial role in activation of T cells.

Medigene´s CD40L-CD28 costimulatory switch receptor may contribute to an enhancement of cellular immune responses in several ways.

> CD40L expressed on activated T cells and CD40 expressed on DC transmits a signal to the antigen presenting cells that results in upregulation of costimulatory molecules and further stimulation of optimal T cell responses.

> CD40-expressing tumor cells can be subject to apoptosis by direct interaction with CD40L-CD28-engineered T cells independent of MHC/peptide-specific targeting.

> CD40 is found in the TME of the tumor endothelium, where engagement with CD40L-CD28-engineered T cells enables upregulation of adhesion molecules, thereby improving T cell infiltration into tumors.

Thus, the CD40L-CD28 costimulatory switch receptor acts via DCs and other non-tumor cells and may provide complementary effects to other switch receptors that exert their effects mainly via PD-1 expressing T cells.

About PD1-41BB Costimulatory Switch Receptor

Checkpoint inhibition via PD-1/PD-L1 pathway:

Cells of solid tumors are sensitive to killing by activated T cells but can escape this killing activity by producing inhibitory molecules known as ‘checkpoint proteins’, such as the 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 is an adaptive immune resistance mechanism for tumors that can help them survive and grow.

The 4-1BB (CD137) costimulatory signaling pathway:

Effective T cell immune responses to antigens typically require both a primary antigenic stimulation via the T cell receptor (TCR) and costimulatory signals. The intracellular signaling domains of the 4-1BB protein offer a well-characterized pathway to costimulation and enhanced T cell responses.

Medigene’s PD1-41BB switch receptor turns the tumor’s attempted self-defense mechanism against the tumor by substituting the inhibitory signaling domain of PD-1 with the activating signaling domain of 4-1BB. Therefore, instead of inactivating T cells, the switch receptor delivers an activating signal to TCR-T cells. PD1-41BB-modified TCR-T cells proliferate strongly in the presence of PD-L1-positive tumor cells and kill more tumor cells upon repeated exposure. Additionally, switch receptor signals enable TCR-T cells to function better with low levels of glucose or high levels of TGFß, two conditions 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.

Medigene AG

Pamela Keck
Phone: +49 89 2000 3333 01
E-mail: investor@medigene.com

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