Interleukin-12 (IL-12) is a potent cytokine that displays remarkable anti-tumour activity, yet its clinical development has been hampered by severe toxicities associated with the activation of circulating immune cells. Here, we present pre-clinical data on a series of reduced potency IL-12 Fc fusion proteins that have been engineered to minimise toxicity whilst retaining on-tumour activity and exhibiting an enhanced pharmacokinetic profile.