Studying novel immunomodulatory agents

‘Our challenge models, such as vaccination with the neoantigen keyhole limpet hemocyanin (KLH) and lipopolysaccharides (LPS) exposure, provide valuable mechanistic insights into the effects of various immunomodulatory compounds’, says Clinical Scientist Anouk Meijs. She was involved in two studies in which such compounds were investigated in more detail, an IL-2 mutein and a compound that simultaneously inhibits three different cytokines.

The effects of IL-2 show once again how complex the functioning of the immune system can be. IL-2 is pro-inflammatory in higher doses, as it activates the effector T-cells of the immune system. In lower doses, however, it has an inhibiting effect on T-cell-mediated inflammatory responses through the activation of regulatory T-cells. ‘Currently, immunomodulatory compounds are being developed that preferentially activate regulatory T-cells and that have a longer half life than the body's own IL-2,’ says Meijs.

To explore this mechanism, healthy volunteers were first vaccinated with KLH, followed by an intradermal KLH challenge. This provided valuable pharmacodynamic data, offering insights into the compound’s immunomodulatory effects prior to advancing to phase 2 trials.

The Immunology Group also studied a compound designed to inhibit three cytokines simultaneously—a first in clinical development. “While therapies that target one of these cytokines already exist, this is the first compound to block all three,” says Meijs. First-in-human studies had been completed elsewhere, and CHDR’s role focused on elucidating the drug’s mechanism of action in healthy volunteers.

In collaboration with the sponsor, the team selected a dual-challenge model combining intradermal LPS administration and topical application of imiquimod. Participants were treated with the investigational compound or placebo. Two other approved drugs were used as comparators. The effect of the various agents was mapped using various instruments in CHDR’s Dermatoolbox, including imaging techniques, suction blisters and skin biopsies.

‘The initial imaging results are promising,’ Meijs reports. ‘We soon hope to analyse the blister fluid and the biopsies, which will provide deeper insights into the immune-modulating effects of the compound. For me, it’s really interesting to conduct a proof of mechanism study like this and provide the client with more detailed information about the effects of the compound on the immune system.’