Harnessing HERA-LIGHT: Advancing T Cell Immunotherapy through Hexavalent HVEM Agonism

LIGHT (TNFSF14) is a member of the tumor necrosis factor superfamily that plays a crucial role in modulating immune cell activity, particularly T cells. HVEM, a receptor for LIGHT, can provide a co-stimulatory signal that aids in T cell activation and expansion, which is beneficial for tumor clearance. Apogenix's HERA technology platform has created a novel HERA-LIGHT construct, a hexavalent TNFSF fusion protein designed to mimic the natural receptor binding mode and stimulate T cells without reliance on Fcγ-receptor crosslinking.

The HERA-LIGHT construct is engineered to closely imitate the natural ligand, with a high capacity for receptor clustering. It consists of a single-chain polypeptide containing the necessary sequences to form a functional trivalent receptor binding domain (RBD). By attaching a silenced IgG1 Fc-domain to the RBD's C-terminus, HERA-LIGHT is created as a hexavalent fusion protein. It has been expressed in CHO suspension cells and purified to produce a homogeneous, aggregate-free product.

HERA-LIGHT has demonstrated the ability to bind both human and murine HVEM receptors, as confirmed by ELISA. It exhibits excellent stability under various stress conditions and has a terminal half-life of 36.5 hours in CD1-mice, indicating a fast clearance rate that could be advantageous for combination therapies and reducing side effects.

In vitro tests have shown that HERA-LIGHT promotes the activation and proliferation of naive effector T cells (Teff), as evidenced by CFSE dilution upon stimulation with anti-CD3 antibody. Importantly, HERA-LIGHT can prevent the suppression of Teff proliferation by regulatory T cells (Treg). In vivo, a murine surrogate of HERA-LIGHT significantly inhibited tumor growth in a CT-26 colorectal cancer model.

In conclusion, HERA-LIGHT's hexavalent design allows for efficient co-stimulation of Teff, even in the presence of Treg cells, and is independent of secondary crosslinking events. As a pure agonist, HERA-LIGHT stands out from current antibody-based therapies and holds promise as a candidate for cancer immunotherapy.