IMM20324, a first-in-class, anti-interleukin-38 monoclonal antibody, rescues myeloid cell activation in vitro and induces robust anti-tumor responses in vivo

Immune checkpoint inhibitors that overcome T cell suppressive mechanisms in tumors have revolutionized the treatment of cancer. However, therapies targeting innate immune cell subsets that orchestrate adaptive immune responses could significantly improve the incidence of clinical response by more effectively activating a multi-lineage response to the tumor. Here, we show that IMM20324, an antibody that binds and neutralizes IL-38, enhances innate immune cell function in vitro and inhibits tumor growth in vivo. IMM20324 binds human, mouse and cynomolgus IL-38 and inhibits the binding of IL-38 to its putative receptors, IL1RAPL1 and IL-36R. In vivo, IMM20324 administration leads to inhibition of tumor growth and improved survival in two different syngeneic tumor models. Importantly, while IMM20324 targets innate immune cells, antibody treatment leads to the induction of immunological memory responses that induce tumor rejection following tumor rechallenge. Together, our data support the hypothesis that IL-38 plays an important role in tumor immunity and that therapies targeting IL-38 could reverse suppressive mechanisms in tumor microenvironment. IMM20324 demonstrated favorable in vitro potency and in vivo efficacy and therefore represents a promising development candidate with the potential to treat multiple cancers. Citation Format: John P Dowling, Pavel A Nikitin, Fang Shen, James P Finn, Nirja Patel, Cezary Swider, Jamie Steele, Halley Shukla, Matthew K Robinson, Karen Lundgren, Benjamin C Harman. IMM20324, a first-in-class, anti-interleukin-38 monoclonal antibody, rescues myeloid cell activation in vitro and induces robust anti-tumor responses in vivo [abstract]. In: Proceedings of the AACR-NCI-EORTC Virtual International Conference on Molecular Targets and Cancer Therapeutics; 2021 Oct 7-10. Philadelphia (PA): AACR; Mol Cancer Ther 2021;20(12 Suppl):Abstract nr LBA022.