Pre-existing antibody-mediated adverse effects prevent the clinical development of a bacterial anti-inflammatory protein

Dis Model Mech. 2020 Sep 28;13(9):dmm045534. doi: 10.1242/dmm.045534.


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 the 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, which are possibly related to the presence of relatively high circulating anti-CHIPS antibodies and suggest an inflammatory response. 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.

Keywords: C5aR chemotaxis; CHIPS; Clinical trials; Humanized mouse; Immune complex.

Publication types

  • Randomized Controlled Trial
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adolescent
  • Adult
  • Animals
  • Antibodies, Bacterial / adverse effects*
  • Antigen-Antibody Complex / metabolism
  • Bacterial Proteins / metabolism*
  • Biomarkers / blood
  • Cell Movement
  • Complement C5a / metabolism
  • Disease Models, Animal
  • Healthy Volunteers
  • Humans
  • Male
  • Mast Cells / enzymology
  • Mice, Transgenic
  • Middle Aged
  • Neutrophils / metabolism
  • Receptor, Anaphylatoxin C5a / metabolism
  • Tryptases / blood
  • Young Adult


  • Antibodies, Bacterial
  • Antigen-Antibody Complex
  • Bacterial Proteins
  • Biomarkers
  • C5AR1 protein, human
  • Receptor, Anaphylatoxin C5a
  • chemotaxis inhibitory protein, Staphylococcus aureus
  • Complement C5a
  • Tryptases