Introduction
Interleukin-12 (IL-12) is a potent inflammatory cytokine that exhibits broad acting immunomodulatory effects including the activation and proliferation of T and NK cells, induction of Th1 differentiation, inhibition or reprogramming of suppressive cells such as TAMs and Tregs, and induction of MHC-I expression on tumour cells (Figure 1). While IL-12 displays remarkable anti-tumour activity in syngeneic tumour models, its clinical development has been hampered by severe toxicities associated with the activation of circulating immune cells. Here, we present a series of reduced potency IL-12 Fc fusion proteins engineered to minimise toxicity whilst retaining on-tumour activity and exhibiting an enhanced pharmacokinetic profile.
Conclusions:
- A series of human IL-12 Fc reduced potency variants were generated in a monovalent Fc fusion format.
- Reduced potency IL-12 Fc variants demonstrate superior pharmacokinetics and exhibit robust anti-tumour activity in in vivo models, whilst reducing toxicity associated with the activation of circulating immune cells.
- Compared to WT IL-12 Fc, reduced potency variants increase the levels of proinflammatory cytokines (e.g. IFN-ɣ) in the tumour relative to the periphery, indicating that potency reductions in IL-12 are associated with an increase in its therapeutic index.
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