Aims Interleukin-21 (IL-21) is a cytokine of common γ chain family, predominantly produced by activated CD4 T cells. IL-21 has broad immuno-stimulatory properties required for antibody affinity maturation and memory formation, as well as for maintenance of cytotoxic immunity from exhaustion during chronic infection. Indeed, recombinant human IL-21 (hIL-21) has shown great promise in phase I and II clinical trials to boost immunity in cancer immunotherapies. We took a novel approach to develop a unique agonistic antibody, 2P2 to hIL-21, which enhances bioactivity of hIL-21 to 10–100 folds in vitro and significantly prolonged half-life of hIL-21 in vivo. This project aims to identify the mechanism of the super-agonistic activityof 2P2 using bio-assays and crystallography. In addition, the application of anti-infection and anti-tumour functions of this super-agonistic antibody will be tested in human cell culture and in vivo mouse models. Methods Mechanisms of 2P2 superagonistic property will be studied by epitope mapping and crystallography. To investigate the in vivo superagonistic activity of 2P2, human IL-21R (hIL-21R) knock in mice have been generated by replacing (knock-in) the endogenous mouse IL-21R with hIL-21R. These hIL21R KI mice are being used to determine the half-life of 2P2/IL-21 and to test the activity of 2P2 in anti-infection and anti-tumour models. To investigate therapeutic applicability of 2P2, anti-HIV activity in the peripheral blood mononuclear cells (PBMC) from HIV infected patients will be determined in the presence of hIL-21/2P2. Results and conclusions 2P2 binds to the epitope proximate to hIL-21/hIL-21R binding interface and the structural analysis suggests it might stabilize the ligand-receptor binding. Functionally, 2P2 has been shown to prolong the half-life of IL-21 and promote cytotoxicity in vivo. In parallel, 2P2 is able to enhance the cytotoxicity of NK cells and CD8 T cells in PBMCs from HIV-infection patients. All together, this study reveals a new class of superagonistic antibody with broad application potential.