Keiko Kasutani

Anti-IL-31 receptor antibody is shown to be a potential therapeutic option for treating itch and dermatitis in mice

IL‐31, which is described as a pruritogenic cytokine, is linked to the itching that is associated with allergic and non‐allergic eczema, but the precise pruritogenic mechanism of IL‐31 and its potential as a therapeutic target for atopic dermatitis (AD) have not been determined.

Cynomolgus monkey model of interleukin-31-induced scratching depicts blockade of human interleukin-31 receptor A by a humanized monoclonal antibody

Scratching is an important factor exacerbating skin lesions through the so‐called itch‐scratch cycle in atopic dermatitis (AD). In mice, interleukin (IL)‐31 and its receptor IL‐31 receptor A (IL‐31RA) are known to play a critical role in pruritus and the pathogenesis of AD; however, study of their precise roles in primates is hindered by the low sequence homologies between primates and mice and the lack of direct evidence of itch sensation by IL‐31 in primates. We showed that administration of cynomolgus IL‐31 induces transient scratching behaviour in cynomolgus monkeys and by that were able to establish a monkey model of scratching. We then showed that a single subcutaneous injection of 1 mg/kg nemolizumab, a humanized anti‐human IL‐31RA monoclonal antibody that also neutralizes cynomolgus IL‐31 signalling and shows a good pharmacokinetic profile in cynomolgus monkeys, suppressed the IL‐31‐induced scratching for about 2 months. These results suggest that the IL‐31 axis and IL‐31RA axis play as critical a role in the induction of scratching in primates as in mice and that the blockade of IL‐31 signalling by an anti‐human IL‐31RA antibody is a promising therapeutic approach for treatment of AD. Nemolizumab is currently under investigation in clinical trials.

Effective screening method of agonistic diabodies based on autocrine growth

Agonistic diabodies that mimic the function of natural ligands are expected to increase the value of therapeutic antibodies. We have developed a method that detects agonistic diabodies based on their ability to transduce growth signals through receptors, thereby permitting cytokine-independent growth of BaF/3-derived cytokine-dependent cells. Retrovirus-mediated expression of the diabody in cytokine-dependent cells was followed by selection of clones for growth in the absence of cytokine. A diabody library derived from splenocytes of human Mpl immunized mice was constructed. Infection of cells with viral particles led to the isolation of over 500 autonomously growing clones whose cultured supernatants showed agonistic activities against Mpl. Genome-integrated diabodies were cloned; representative clone AB317 showed agonistic activities as potent as a natural ligand and cross-reactive against mouse Mpl.