A novel strategy to generate immunocytokines with activity-on-demand using small molecule inhibitors

• Published in: EMBO molecular medicine 2024-04, Vol.16 (4), p.904-926
• Main Authors: Rotta, Giulia, Gilardoni, Ettore, Ravazza, Domenico, Mock, Jacqueline, Seehusen, Frauke, Elsayed, Abdullah, Puca, Emanuele, De Luca, Roberto, Pellegrino, Christian, Look, Thomas, Weiss, Tobias, Manz, Markus G, Halin, Cornelia, Neri, Dario, Dakhel Plaza, Sheila
• Format: Article
• Language: English
• Subjects: Antibody-Cytokine Fusions; Biomedical and Life Sciences; Biomedicine; Cancer Immunotherapy; EMBO03; EMBO08; EMBO19; Molecular Medicine; Small Molecule Inhibitors; Tolerability; Tumor Targeting
• ISSN: 1757-4684; 1757-4676; 1757-4684
• DOI: 10.1038/s44321-024-00034-0

Cytokine-based therapeutics have been shown to mediate objective responses in certain tumor entities but suffer from insufficient selectivity, causing limiting toxicity which prevents dose escalation to therapeutically active regimens. The antibody-based delivery of cytokines significantly increases the therapeutic index of the corresponding payload but still suffers from side effects associated with peak concentrations of the product in blood upon intravenous administration. Here we devise a general strategy (named “Intra-Cork”) to mask systemic cytokine activity without impacting anti-cancer efficacy. Our technology features the use of antibody-cytokine fusions, capable of selective localization at the neoplastic site, in combination with pathway-selective inhibitors of the cytokine signaling, which rapidly clear from the body. This strategy, exemplified with a tumor-targeted IL12 in combination with a JAK2 inhibitor, allowed to abrogate cytokine-driven toxicity without affecting therapeutic activity in a preclinical model of cancer. This approach is readily applicable in clinical practice. Synopsis A novel strategy is presented to control adverse events related to tumor-targeted cytokine therapy. The approach features the use of antibody-cytokine fusions, localizing at the neoplastic site, in combination with selective inhibitors of the cytokine signaling, which rapidly clear from the body. This strategy, exemplified with a tumor-targeted IL12 in combination with a JAK2 inhibitor (Ruxolitinib), allowed to abrogate cytokine-driven toxicity without affecting therapeutic activity in a preclinical model of cancer. The transient inhibition of L19-mIL12 signaling helped to control systemic cytokine release, body weight loss, and hepatotoxicity. The use of suitably spaced administrations of Ruxolitinib represents a general avenue to maximize the clinical utility of antibody cytokine fusions with a long residence time at the neoplastic site. The approach devised in this work is readily applicable in clinical practice. A novel strategy is presented to control adverse events related to tumor-targeted cytokine therapy. The approach features the use of antibody-cytokine fusions, localizing at the neoplastic site, in combination with selective inhibitors of the cytokine signaling, which rapidly clear from the body.