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

Authors: Jiaxi Wu, Nicolin Bloch, Aaron Y. Chang, Ramandeep Bhavsar, Qingqing Wang, Alison Crawford, David J. DiLillo, Kristin Vazzana, Katja Mohrs, Drew Dudgeon, Supriya Patel, Hassan Ahmed, Vidur Garg, Michael Amatulli, Olivia Q. Antao, Yuetian Yan, Shunhai Wang, Willy Ramos, Pamela Krueger, Christina Adler, Min Ni, Yi Wei, Chunguang Guo, Lynn E. Macdonald, Tammy Huang, Erica Ullman, Aynur Hermann, George D. Yancopoulos, Andrew Murphy, Samuel Davis, William C. Olson, John Lin, Eric Smith, Tong Zhang - Cell Reports Medicine 2024 cited by 27

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.