Abstract 4227: NL-201, a de novo agonist of IL-2 and IL-15 receptors, demonstrates antitumor activity in preclinical B cell lymphoma models

Abstract NL-201 is a computationally-designed IL-2/IL-15 cytokine mimetic under investigation in a phase 1 clinical trial for patients with solid tumors. This de novo protein signals through the IL-2Rβ/ɣ complex in an IL-2Rα-independent fashion, supporting immune function of both T cells and natural killer (NK) cells. In syngeneic tumor models of solid tumors, NL-201 demonstrates marked antitumor activity through multiple mechanisms of action, including upregulation of granzyme B in cytotoxic CD8+ T cells and NK cells. Here, we further explored the therapeutic potential of NL-201 in preclinical models of B cell malignancies. In cell-based studies, NL-201 augmented antibody-dependent cellular cytotoxicity (ADCC) of Toledo DLBCL (diffuse large B cell lymphoma) cells incubated with human NK cells and CD20 antibodies. Importantly, direct activation by NL-201 was specific to NK cells and did not impact STAT5 phosphorylation nor proliferation of the tested malignant cells. The administration of NL-201 monotherapy in mice bearing A20 B cell lymphoma syngeneic tumors yielded robust inhibition of tumor growth. Tumor xenografts from implanted Pfeiffer cells have also been evaluated to understand the activity of NL-201 in a model closely resembling DLBCL physiology. In summary, NL-201 is active as a single agent and in combination with CD20-targeted therapies in vitro, as well as demonstrating monotherapy activity in in vivo preclinical models of B cell malignancies as well as in combination with checkpoint inhibitors. The NL-201 enhancement of cytotoxicity by CD8+ T cells and NK cells supports additional exploration aimed at optimizing combinatorial approaches. These findings will inform the design of planned clinical studies with NL-201 in patients with B-cell lymphomas and other hematological malignancies. Citation Format: Justin Huard, Christie Mortales, Alex Chen, Ryan Swanson, Carl Walkey, Bill Arthur. NL-201, a de novo agonist of IL-2 and IL-15 receptors, demonstrates antitumor activity in preclinical B cell lymphoma models [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 4227.