Abstract IA07: Engineered cytokine-antibody fusion proteins for targeted stimulation of anti-cancer immunity

Abstract Immunotherapies have revolutionized the cancer treatment landscape by empowering activation of the patient’s own immune system to fight disease. One of the first immunotherapies to receive FDA approval for cancer treatment was interleukin-2 (IL-2), a multi-functional cytokine that potently stimulates immune cell growth and activity. IL-2 has shown tremendous potential as an anti-cancer therapeutic and elicits complete and durable responses in 5-10% of treated patients. However, clinical use of IL-2 has been limited by severe toxicities, counterproductive activation of regulatory T cells (Tregs), and the cytokine’s vanishingly short serum half-life (<5 min). Complexation of IL-2 with certain anti-IL-2 antibodies has been shown to selectively bias cytokine activity towards immune effector cells (i.e., effector T cells and natural killer [NK] cells) while concurrently extending its serum half-life, leading to potent antitumor activity in mice in the absence of adverse effects. Unfortunately, clinical development of a mixed cytokine/antibody complex is impeded by logistical hurdles such as dosing optimization, as well as concerns regarding complex stability. We overcame these challenges by engineering a single-agent IL-2/antibody fusion protein (termed an immunocytokine) that selectively stimulates immune effector cells. We demonstrated the efficacy of our immunocytokine in biasing the immune response in cellular and animal models. We achieved successful tumor targeting of our molecule through fusion to an extracellular matrix-binding protein domain and showed that the resulting immunocytokine induced robust antitumor activity without inducing toxicity in multiple mouse tumor models, both alone and in combination with immune checkpoint blockade. Overall, our strategy offers insight into the design and development of translationally promising IL-2 therapies with versatility to treat a range of cancer types. Citation Format: Jamie B Spangler. Engineered cytokine-antibody fusion proteins for targeted stimulation of anti-cancer immunity [abstract]. In: Proceedings of the AACR IO Conference: Discovery and Innovation in Cancer Immunology: Revolutionizing Treatment through Immunotherapy; 2025 Feb 23-26; Los Angeles, CA. Philadelphia (PA): AACR; Cancer Immunol Res 2025;13(2 Suppl):Abstract nr IA07.