Bacterial pathogens have evolved to secrete strong anti-inflammatory proteins that target the immune system. It was long speculated whether these virulence factors could serve as therapeutics in diseases in which abnormal immune activation plays a role. We adopted the secreted Chemotaxis Inhibitory Protein of Staphylococcus aureus (CHIPS) as a model virulence factor-based therapeutic agent for diseases in which C5aR1 stimulation plays an important role. We show that administration of CHIPS in human C5aR1 knock-in mice successfully dampens C5a mediated neutrophil migration during immune complex initiated inflammation. Subsequent CHIPS toxicology studies in animal models were promising. However, during a small phase-I trial, healthy human volunteers showed adverse effects directly after CHIPS administration. Subjects showed clinical signs of anaphylaxis with mild leukocytopenia and increased C-reactive protein concentrations, suggesting an inflammatory response, which are possibly related to the presence of relatively high circulating anti-CHIPS antibodies. Even though our data in mice show CHIPS as a potential anti-inflammatory agent, safety issues in human subjects temper the use of CHIPS in its current form as a therapeutic candidate. The use of staphylococcal proteins, or other bacterial proteins, as therapeutics or immune-modulators in humans is severely hampered by pre-existing circulating antibodies.
Pre-existing antibody-mediated adverse effects prevent the clinical development of a bacterial anti-inflammatory protein
Currently Viewing Accepted Manuscript - Newer Version Available
Angelino T. Tromp, Yuxi Zhao, Ilse Jongerius, Erik C. J. M Heezius, Pauline Abrial, Maartje Ruyken, Jos A. G. van Strijp, Carla J. C. de Haas, András N. Spaan, Kok P. M. van Kessel, Thomas Henry, Pieter-Jan A. Haas; Pre-existing antibody-mediated adverse effects prevent the clinical development of a bacterial anti-inflammatory protein. Dis Model Mech 2020; dmm.045534. doi: https://doi.org/10.1242/dmm.045534
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