| Summary: | IL-2 is a pleiotropic cytokine that plays an essential role in the survival, expansion, and function of CD8 T cells, regulatory T cells (Tregs), and natural killer (NK) cells. Previous studies showed that binding IL-2 with an anti-IL-2 monoclonal antibody (mAb) with a particular specificity could block its interaction with IL-2Rα, which is mainly expressed on Tregs. This selectivity can enhance the anti-tumor effects of IL-2 by activating CD8 T and NK cells, while disfavoring Treg stimulation. Based on this, we newly developed a series of anti-human IL-2 (hIL-2) mAbs (TCB1-3) that selectively stimulate CD8 T and NK cells without overtly activating Tregs. Among them, the hIL-2/TCB2 complex (hIL-2/TCB2c) exerted the best efficacy by inducing a prodigious expansion of host memory phenotype (MP) CD8 T (60-fold) and NK cells (18-fold) with less efficient Treg proliferation (5-fold). As a result, there was an average eightfold increase in the ratio of MP CD8 to Tregs. Accordingly, hIL-2/TCB2c strongly inhibited the growth of B16F10, MC38, and CT26 tumors. More remarkably, hIL-2/TCB2c showed synergy with checkpoint inhibitors such as anti-CTLA-4 or PD1 antibodies, and resulted in almost complete regression of implanted tumors and resistance to secondary tumor challenge. For direct clinical use, we generated a humanized form of TCB2 that had equal immunostimulatory and anti-tumor efficacy as a murine one. Collectively, these results show that TCB2 can provide a potent immunotherapeutic modality either alone or together with checkpoint inhibitors in cancer patients.
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