Multimeric complexes to unlock the therapeutic potential of innate immunity against chronic respiratory infections

The Pseudomonas aeruginosa (P. aeruginosa) bacterium and the Aspergillus fumigatus (A. fumigatus) fungus are associated with persistent and chronic, or recurrent and acute, respiratory infections. P. aeruginosa can thrive as a biofilm at the surface of bronchial airways easing the colonization of the host and resulting in a chronic infection, primarily observed in patients suffering from cystic fibrosis (CF) or chronic obstructive pulmonary disease (COPD). The exopolysaccharide Psl contributes to biofilm formation, immune evasion, inflammation, and damage to the lung. In CF patients, P. aeruginosa is frequently associated with A. fumigatus fungi (≈ 60% cases of over 12 year-old subjects) resulting in a worse prognosis, as it has been observed in COVID-19 patients in intensive care units. Both pathogens display resistance to a variety of antibiotics or antifungals and have now been classified as critical “priority one” pathogens by the WHO.

Antibody-based therapeutics will offer novel perspectives for addressing chronic respiratory infections and counteract antimicrobial/antifungal resistance. We have developed multimeric complexes (CoMiX) that activate the complement pathways at the surface of P. aeruginosa using a scFv targeting the exopolysaccharide Psl, as well as trispecific Natural Killer (NK) cell engagers targeting two surface receptors of NK cells, NKG2D and SLAMF-7, as well as Psl from the bacterium. Both approaches induce killing of bacteria and inhibit acute infection.

We aim to validate the pre-clinical efficacy of therapeutic approaches against lung’s invasive and chronic diseases. We expect to foster innovative pharmaceutical breakthroughs that could be directly translated into patients in the near future.