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

  • Cell Rep Med. 2024 Oct 15;5(10):101747. doi: 10.1016/j.xcrm.2024.101747.
Jiaxi Wu  1 ,  Nicolin Bloch  2 ,  Aaron Y Chang  2 ,  Ramandeep Bhavsar  2 ,  Qingqing Wang  2 ,  Alison Crawford  2 ,  David J DiLillo  2 ,  Kristin Vazzana  2 ,  Katja Mohrs  2 ,  Drew Dudgeon  2 ,  Supriya Patel  2 ,  Hassan Ahmed  2 ,  Vidur Garg  2 ,  Michael Amatulli  2 ,  Olivia Q Antao  2 ,  Yuetian Yan  2 ,  Shunhai Wang  2 ,  Willy Ramos  2 ,  Pamela Krueger  2 ,  Christina Adler  2 ,  Min Ni  2 ,  Yi Wei  2 ,  Chunguang Guo  2 ,  Lynn Macdonald  2 ,  Tammy Huang  2 ,  Erica Ullman  2 ,  Aynur Hermann  2 ,  George D Yancopoulos  2 ,  Andrew J Murphy  2 ,  Samuel Davis  2 ,  William C Olson  2 ,  John C Lin  2 ,  Eric Smith  2 ,  Tong Zhang  2
Affiliations
  • 1. Regeneron Pharmaceuticals, Inc., Tarrytown, NY 10591, USA. Electronic address: [email protected].
  • 2. Regeneron Pharmaceuticals, Inc., Tarrytown, NY 10591, USA.
Abstract

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.

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