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

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

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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