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Abstract IL-2 is a powerful cytokine central to the generation of an effective immune response. However, its use in cancer immunotherapy has been limited by toxicities arising from its broad activity as well as the narrow patient population in which efficacy is seen. To address these limitations, many strategies have been pursued including IL-2 attenuation and targeting of IL-2 activity. These approaches, however, retain unacceptable toxicity and/or are not targeted to the appropriate cell populations. Using a novel approach that takes advantage of the ability of an antibody to bind specifically and competitively to two distinct antigens, we have generated a conditionally active cLAG3-IL2 therapeutic that targets IL-2 to LAG3+ cells while remaining inert on IL-2Rβγ+ cells lacking LAG3 expression, even at high treatment doses. As a marker of antigen-activated and tumor-specific T cells, LAG3 is an ideal target toward which to direct IL-2 activity. In vitro, using both reporter cell lines and receptor binding assays, the regulated cLAG3-IL2 demonstrates 100 fold difference in activity in the presence or absence of LAG3. In primary immune cells, regulated cLAG3-IL2 preferentially induces IL-2 cis-signaling in activated human LAG3+ CD8 T cells compared to LAG3- T cells. In mouse syngeneic tumor models, cLAG3-IL2 inhibits tumor growth while avoiding clinical signs of IL-2-mediated toxicity at doses well above the level where the non-regulated IL2 is toxic. Additionally, cLAG3-IL2 does not induce expansion of circulating LAG3- IL-2Rβγ+ cell populations, including NK cells and LAG3- T cells. In the TME, cLAG3-IL2 drives the expansion and activation of tumor-specific CD8+ T cells. Furthermore, cLAG3-IL2 demonstrates robust combinatorial activity with anti-PD1. These results demonstrate the strength of the Bonum platform, currently applied to multiple target/effector pairs including PD1, PDL1, ATP, LRRC15 and effectors IFNα, IL12 and TGFβ inhibition, and support the clinical development of our conditionally active cLAG3-IL2. Citation Format: Justin Killebrew, Shannon Okada, Lynn Amon, David Bienvenue, Laura Carlucci, David Colby, Wendy Curtis, Kendyl Daniels, Alton Etheridge, Zane Kraft, Jamie Nguyen, Sandra Notonier, Jacqueline Pham, Megan Sprague, Kerri Thomas, Diane Hollenbaugh, John Mulligan. A novel method for generating regulated cytokine therapeutics: Safety and activity of a conditionally active cLAG3-IL2 capable of delivering IL2 to LAG3+ cells while remaining inert on LAG3- cells abstract. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 1 (Regular Abstracts) ; 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84 (6Suppl): Abstract nr 4062.
Killebrew et al. (Fri,) studied this question.