WTX-124, a Conditionally Activated Wild-Type IL2, Maximizes the Therapeutic Index of IL2, Unlike “Non-Alpha” Muteins

High-dose interleukin 2 (HD IL2) produces durable responses in patients with advanced cancer, but its use is limited by life-threatening toxicities such as vascular leak syndrome (VLS). To improve the therapeutic index for IL2, a class of IL2 molecules has been engineered to not bind the alpha subunit (CD25) of the high-affinity IL2 receptor. Although these "non-alpha" muteins do not cause VLS, they have other dose-limiting toxicities and have yet to demonstrate antitumor activity comparable with HD IL2. We therefore investigated the potential of a tumor-activated, wild-type IL2 molecule (WTX-124) to improve IL2 tolerability without compromising its efficacy. In mouse models, CD25 engagement by wild-type IL2 was required for optimal activation of tumor-specific CD8+ T cells and for antitumor efficacy. Furthermore, wild-type IL2 was nearly 100-fold more potent than non-alpha IL2 in activating primary human tumor-infiltrating lymphocytes (TIL), even with FoxP3+ regulatory T cells present. Pharmacokinetic-receptor occupancy (PK/RO) modeling showed that by masking wild-type IL2 in the periphery, WTX-124 produces high RO on TILs but low RO on peripheral lymphocytes, unlike non-alpha IL2s. These findings therefore identify the conditional activation of wild-type IL2 as a promising engineering strategy to improve IL2 tolerability without compromising its antitumor activity.