Apogenix presents data on novel Hexavalent TNF receptor agonists

Agonists for GIT, CD27 and CD40 receptors in development for cancer immunotherapy exhibit significant in vitro- and in vivo activities.

The GIT receptor (GITR) plays an important role in initiating the immune response in the lymph nodes and in maintaining the immune response in the tumour tissue. The in vitro and in vivo properties of HERA-GITR ligands were studied in primary immune cells and different mouse models. HERA-GITR-ligands demonstrated excellent in vivo stability. Their ability to enhance proliferation and activation of naïve CD4+ and CD8+ T cells and to induce memory formation render them as attractive candidates for immunotherapeutic treatments of cancer.

CD27L is a potent co-stimulatory molecule that drives T cell activation and survival through binding to its receptor (CD27). This interaction can be exploited to improve an anti-tumor immune response. Binding of HERA-CD27-ligand to CD27 triggered a strong T cell expansion in vitro and in vivo. In two mouse tumour models treatment with HERA-CD27-ligand led to a dose-dependent inhibition of tumour growth and stimulated enhanced memory formation in both CD4+ and CD8+ T cells. With their potent immune cell-driven anti-tumour efficacy, HERA-CD27-ligands represent suitable candidates for further preclinical and clinical development for cancer therapy.

In the humoral immune system, the CD40 receptor plays a central role in the activation and maturation of B lymphocytes. HERA-CD40L could activate the CD40 signaling cascade in B cells and monocytes, thereby triggering direct cytolytic activation and proliferation of CD4+ T cells as well as macrophage differentiation. Unlike bivalent CD40 antibodies or trivalent CD40L-based agonists, the hexavalent HERA-CD40L forms highly clustered signaling complexes with superior biological activity and without the need for Fc-receptor-mediated crosslinking. Our data demonstrate that HERA-CD40L is a novel candidate for cancer immunotherapy with exceptional features.