Self-assembling sequentially administered tumor targeted Split IL-12p35 and p40 subunits to improve the therapeutic index of systemically delivered IL-12 therapy for cancer

Résumé fourni par la source

IL-12, also called IL-12p70, is a highly potent, proinflammatory heterodimeric cytokine that can mediate many beneficial anti-tumor effects. In preclinical studies, recombinant IL-12, as well as IL-12 gene therapies, have demonstrated notable anti-tumor results across various tumor types; however, IL-12 clinical benefit has been limited by its poor tolerability at potentially efficacious doses. We have developed a novel approach to mitigate the toxicity of IL-12 by engineering tumor-targeted split IL-12 that preferentially localizes IL-12 activity to the tumor microenvironment. The functionally inactive IL-12 subunits, p35 and p40, are separately fused to antibody fragments targeting a highly expressed tumor-associated antigen, uPAR. The goal of this strategy is to drive assembly and activity of the IL-12 heterodimer into the tumor site through sequential administration of the targeted subunits, reducing systemic exposure and thereby potentially reducing associated toxicities. We use in vitro activity assays along with in vivo pharmacokinetic and pharmacodynamic studies in mice and non-human primates to demonstrate that the split IL-12 anti-uPAR fusions are capable of assembly and activity in vivo. The targeted p35 and p40 subunits are capable of complexing to form IL-12p70 and inducing STAT4 phosphorylation when applied to cultured immune cells, indicating in vitro IL-12 activity. Furthermore, sequential administration of subunits in in vivo mouse models demonstrates rapid serum clearance of IL-12 while extending retention in the tumor. Finally, dosing in non-human primates shows molecules are functionally active in vivo. This is a unique strategy with great clinical promise to harness the therapeutic potential of IL-12 while potentially avoiding the toxicity associated with systemic delivery. Schematic of the mural oncology engineered split IL-12 dosing strategy. • Novel engineered IL-12 therapeutic for immune oncology to overcome systemic toxicity. • Split p35 and p40 IL-12 subunits self-assemble to form active p70 in vitro/in vivo. • Assembled p70 induces canonical immune cells and biomarkers in non-human primates. • Dual subunit targeting enhances tumor retention while reducing systemic exposure. • Sequentially delivered tumor targeted split IL-12p70 subunits could improve safety.

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