GenSci120, a humanized PD-1 agonistic monoclonal antibody, enhances the binding of both PD-L1 and PD-L2 to PD-1, and mitigates the symptoms of GVHD in a mouse model

Abstract

Abstract Background: Autoimmune diseases impose tremendous health and economic burden to the individuals and families they affect. The fundamental mechanism of autoimmune diseases is a break in immune tolerance and homeostasis. PD-1 plays an important role in maintaining immune tolerance by antagonizing CD28/TCR signaling in autoreactive T cells. Stimulating the PD-1 co-inhibitory pathway by an agonistic antibody would suppress pathogenic immune responses and restore immune homeostasis. Methods: A PD-1 agonistic monoclonal antibody, GenSci120, was generated by Beacon single plasma cell cloning and murine antibody humanization technologies. In vitro T cell inhibition, ADCC and ligand blocking activities of GenSci120 were characterized. In vivo efficacy in a mouse GVHD model and PK in the human FcRn transgenic mice were evaluated. Results: GenSci120 exhibited potent T cell inhibition activity in a luciferase reporter assay and a primary T cell proliferation assay. GenSci120 also showed ADCC activity in an LDH release assay. Remarkably, GenSci120 enhanced the binding of both PD-L1 and PD-L2 to PD-1 in a flow cytometry assay. In a mouse model, GenSci120 significantly alleviated the symptoms of GVHD. Furthermore, GenSci120 demonstrated longer half-life than competitors’ antibodies in the human FcRn transgenic mice. Conclusion: These data suggest the potential of GenSci120 as a novel therapy to treat autoimmune disorders and support the evaluation of this molecule in clinical studies.