Bacterial immune evasion proteins: The therapeutic potential of CHIPS

Tromp, A.; Zhao, Y.; Jongerius, I.; Heezius, E. C.; Abrial, P.; Ruyken, M.; van Strijp, J.; de Haas, C. J. C.; Spaan, A.; van Kessel, K. P. M.; Henry, T.; Haas, P.-J. A.

doi:10.1101/2020.02.25.964908

bioRxiv · 10.1101/2020.02.25.964908

Bacterial immune evasion proteins: The therapeutic potential of CHIPS

Tromp, A.·Zhao, Y.·Jongerius, I.·Heezius, E. C.·Abrial, P.·Ruyken, M.·van Strijp, J.·de Haas, C. J. C.·Spaan, A.·van Kessel, K. P. M.·Henry, T.·Haas, P.-J. A.

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Abstract

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 believed to be related to the presence of relatively high circulating anti-CHIPS antibodies. Even though our data in mice shows 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.

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Tromp, A., Zhao, Y., Jongerius, I., Heezius, E. C., Abrial, P., Ruyken, M., van Strijp, J., de Haas, C. J. C., Spaan, A., van Kessel, K. P. M., Henry, T., Haas, P.-J. A.. 2020-02-28. Bacterial immune evasion proteins: The therapeutic potential of CHIPS. https://doi.org/10.1101/2020.02.25.964908

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