Exploiting complement for targeted therapies against Pseudomonas aeruginosa infection and breast cancer

Complement is the primary defense mechanism against pathogens and in antitumor immunity. Complement activating Multimeric compleXes (CoMiX), a novel class of antibody-based therapeutics, activate the complement at the surface of pathogens or target cells. In this work, we have evaluated their potential in targeting and eliminating both Pseudomonas aeruginosa (P. aeruginosa) and HER2-positive breast cancer. These multimeric complexes are composed of three distinct functional components: a targeting moiety, an oligomerization domain, and an effector component.
In the context of P. aeruginosa infections, CoMiX were designed to target the Psl-exopolysaccharide of the bacterium. The effector component of CoMiX in this case was either an Fc region, which activated the classical complement pathway and immune cells, or Factor H-related protein 1 (FHR1), which competed with the complement inhibitor Factor H. In vitro studies demonstrated CoMiX's ability to bind to P. aeruginosa isolates, activate complement, and directly kill the bacteria. Importantly, CoMiX was shown to reduce dramatically bacterial load and mortality in a mouse model of acute P. aeruginosa lung infection.
For HER2-positive breast cancer, CoMiX were engineered to target HER2-expressing tumor cells. The effector component in this case was either FHR4, which activated the alternative complement pathway, or a triple Fc dimer, which activated the classical complement pathway and promoted NK cell activation and phagocytosis by macrophages. In vitro studies demonstrated CoMiX's ability to activate complement, induce complement-dependent cytotoxicity, and stimulate immune cell responses. In vivo studies in a xenograft model of human breast cancer showed that CoMiX could effectively inhibit tumor growth and overcome the resistance to trastuzumab.
Overall, these studies highlight the versatility and therapeutic potential of CoMiX in targeting and eliminating both bacterial pathogens and cancer cells. Subsequent research and clinical development are essential to comprehensively assess their potential benefits in patients.