Background Checkpoint inhibitor (CPI) immunotherapy demonstrates modest efficacy against immunologically ‘cold’ or immune-excluded tumors, therefore needs another approach for majority of patients. Although interleukin-12 (IL-12) is a promising antitumor cytokine that enables activation and recruitment of immune cells into tumors, its widespread use in the clinic has been hindered due to severe immune-related adverse events (irAEs). An ideal IL-12 therapy would restrict the proinflammatory effects of IL-12 to the tumor site, while limiting its exposure in the periphery.
Methods Here, we solved the IL-12 toxicity challenge by exploiting the preferential overexpression of proteases (Matrix Metalloproteinases, Serine Proteases) in the tumor to engineer tumor-selective, masked IL-12. A IL-12RB1 receptor-based masking domain was fused to IL-12 p35 domain via a protease-cleavable linker.1
Results Recombinant fusion of masking domain to IL-12 prevented IL-12 from signaling systemically, whereas proteolytic cleavage of the linker domain by tumor-associated enzymes restored the biological activity of IL-12. We demonstrate that intravenously (i.v.) administered, masked IL-12 produces strong therapeutic effects through remodeling the immune-suppressive microenvironment and renders CPI-resistant tumors responsive, while systemic irAEs are eliminated, boosting the therapeutic index of this promising cytokine. In several solid tumour models, the therapeutic effects of masked IL12 were similar to its unmasked wild-type form, yet its toxicity was as low as saline injections. Masked IL-12 synergised with anti-PD-1 antibody for efficacy. We found that addition of human tumour lysates, and not adjacent healthy tissue lysates, cleaved off the mask, induced significant IFNy production and STAT4 phosphorylation, similar to wild-type IL-12. We made fully humanized masked IL-12 molecule already.
Conclusions Masking approach to IL-12 may solve the toxicity issue of IL-12 observed in 1990s clinical trials, while maintaining extremely high anti-tumor effects in immunologically cold tumors (figure 1).
Mansurov A,...Ishihara J, Hubbell JA. Masking the immunotoxicity of interleukin-12 by fusing it with a domain of its receptor via a tumour-protease-cleavable linker. Nature Biomedical Engineering, May 2022
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