A PD-1-targeted, receptor-masked IL-2 immunocytokine that engages IL-2Rα strengthens T cell-mediated anti-tumor therapies

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The clinical use of interleukin-2 (IL-2) for cancer immunotherapy is limited by severe toxicity. Emerging IL-2 therapies with reduced IL-2 receptor alpha (IL-2Rα) binding aim to mitigate toxicity and regulatory T cell (Treg) expansion but have had limited clinical success. Here, we show that IL-2Rα engagement is critical for the anti-tumor activity of systemic IL-2 therapy. A “non-α” IL-2 mutein induces systemic expansion of CD8 + T cells and natural killer (NK) cells over Tregs but exhibits limited anti-tumor efficacy. We develop a programmed cell death protein 1 (PD-1)-targeted, receptor-masked IL-2 immunocytokine, PD1-IL2Ra-IL2, which attenuates systemic IL-2 activity while maintaining the capacity to engage IL-2Rα on PD-1 + T cells. Mice treated with PD1-IL2Ra-IL2 show no systemic toxicities observed with unmasked IL-2 treatment yet achieve robust tumor growth control. Furthermore, PD1-IL2Ra-IL2 can be effectively combined with other T cell-mediated immunotherapies to enhance anti-tumor responses. These findings highlight the therapeutic potential of PD1-IL2Ra-IL2 as a targeted, receptor-masked, and “α-maintained” IL-2 therapy for cancer. • IL-2Rα engagement is important for the anti-tumor activity of systemic IL-2 therapy • Masked IL-2 is attenuated but retains the ability to engage endogenous IL-2Rα • PD1-IL2Ra-IL2 exhibits PD-1-targeting-dependent IL-2 activity and reduced toxicity • PD1-IL2Ra-IL2 shows potent anti-tumor efficacy alone and in combination therapies The clinical use of IL-2 therapy for cancer is limited by severe toxicity. Wu et al. develop a PD-1-targeted, masked, and “α-maintained” IL-2 immunocytokine, PD1-IL2Ra-IL2, which exhibits minimal systemic IL-2 toxicity while delivering robust anti-tumor efficacy both as a monotherapy and in combination with other immunotherapies in preclinical models.

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