Unlocking the Potential of Novel Hexavalent GITR Agonists for T Cell Stimulation and Memory Formation Enhancement

The GITR co-stimulatory receptor is crucial for initiating immune responses in lymph nodes and sustaining them in tumor tissues. It enhances anti-tumor T cell activation and survival upon binding to its ligand and diminishes the inhibitory function of Treg cells, thereby boosting the immune response against tumors. A novel technology named HERA has been developed to target the TNF-receptor superfamily, creating fully human hexavalent fusion proteins that are potent agonists with high clustering capacity. This study presents the in vitro and in vivo characteristics of newly developed hexavalent HERA-GITRL constructs.

In vivo stability was evaluated using serum samples from CD1-mice in a pharmacokinetic study, with drug levels measured via ELISA. Immune cells from healthy donors were used for in vitro testing, where they were analyzed by flow cytometry after isolation. Cells were then exposed to various HERA-GITRL constructs and anti-CD3 in culture media. The activation and memory markers on T cells, proliferation rate, and cytokine levels were assessed.

The study found that slight modifications resulted in three distinct HERA-GITRL drug candidates with unique pharmacokinetic profiles and stability in mice, with a terminal half-life ranging from 61.7 to 200.6 hours. HERA-GITRL significantly increased the expression of activation markers on pan T cells and naive CD4+ T-lymphocytes, along with their proliferation and memory formation. Additionally, there was an elevated level of intracellular TNF-α and IFN-γ in naive CD4+ T-lymphocytes, which was further enhanced by HERA-GITRL.

The conclusion is that HERA-GITRL constructs show excellent in vivo stability and their capacity to stimulate the proliferation and activation of naive CD4+ T cells, as well as induce memory formation, makes them promising candidates for cancer immunotherapy.

The study was presented at the American Association for Cancer Research Annual Meeting in 2017, and the abstract was published in the Cancer Research journal.