Designed protein ‘minibinders’ help treat colitis in mice

Researchers from the Institute for Protein Design and collaborators have designed “minibinders,” or small binding proteins, that may inhibit signaling pathways implicated in autoinflammatory diseases.

The cytokines interleukin-23 (IL-23) and IL-17 have been established as possible targets to treat autoinflammatory disorders like psoriasis and inflammatory bowel disease (IBD). IL-23 is specifically implicated in IBD. But monoclonal antibodies that target these cytokines have to be administered through a needle. This problem presented a niche where Stephanie Berger, David Baker, and colleagues thought their de novo designed minibinders would fit. “Their small size and stability sets them apart from these monoclonal antibodies,” Berger says.

Berger says their minibinders are “extremely stable.” This allows for oral administration rather than by needle because they can survive the harsh acids and proteases of the gastrointestinal tract. Their stability may also confer resistance to proteases that the immune system may use to degrade them. If they resist degradation, they would be less likely to prompt an immune response.

The team tested its oral minibinder for IL-23 in mice that had human-derived IL-23-secreting cells (Cell 2024, DOI: 10.1016/j.cell.2024.05.052). Mice treated with the minibinder showed more improvement in their disease, measured by clinical disease scores, compared with mice that took a placebo. The mice treated with the minibinders showed a numerically greater improvement in clinical scores compared to mice treated with an injected monoclonal antibody called guselkumab, which is in Phase 3 trials.

The researchers did not test the IL-17 minibinder in vivo, and Berger says that is one of the planned next steps. Mopac Biologics, a company founded in part by Berger, is developing the IL-23 minibinder as a possible therapy, and it may adopt the IL-17 minibinder.