Abstract: We discovered that the cytokine interleukin-22 (IL-22) is an efficient natural
inhibitor of cellular stress and are developing IL-22-based biologics. IL-22 is highly
efficacious in metabolic disease with benefits including complete restoration of
glucose tolerance, suppression of fasting hyperinsulinemia/hyperproinsulinemia, and
restoration of insulin sensitivity [1]. Importantly, obese animals treated with IL-22, lost
weight, showed significant improvements in circulating triglycerides and liver function
(AST:ALT ratio), as well as a reduction in lipid accumulation in the liver.
Due to multiple tissues expressing the IL-22-receptor (IL-22RA1) and its role in wound
repair, prolonged administration of IL-22 in patients might lead to off-target effects in
other tissues such as increased cell proliferation in the skin. This is apparent from the
recent Phase I trial with dimerised IL-22, where the 100% of volunteers developed
adverse events which were mainly skin emergent, including eczematous lesions [2].
To overcome this, we have generated a prototype IL-22-based bispecific biologic drug
candidate (IL-22-fusion) which is targeted towards the pancreas and liver. Whilst long
term administration of IL-22-Fc (with a long half-life) induced skin proliferation and
inflammation, our IL-22-fusion did not. Importantly, we demonstrate that liver targeted
IL-22 has enhanced efficacy in the preclinical model of Fatty liver disease; with
improvements in obesity-induced hyperglycaemia, insulin quality and decrease in fat
mass compared with native IL-22. Furthermore, the data shows a reduction in
hepatocyte ER stress (Grp78) and inflammation, reduction in fat/triglyceride
accumulation in the liver and restoration of expression of key hepatic genes involved
in fatty acid metabolism. Our work is now focused on developing this therapeutic for
Phase 1 clinical trials.
1. Hasnain, S.Z., et al., Glycemic control in diabetes is restored by therapeutic
manipulation of cytokines that regulate beta cell stress. Nat Med, 2014. 20(12):
p. 1417-26.
2. Tang, K.Y., et al., Safety, pharmacokinetics, and biomarkers of F-652, a
recombinant human interleukin-22 dimer, in healthy subjects. Cell Mol
Immunol, 2019. 16(5): p. 473-482.