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

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 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.

Source: DMM Disease Models and Mechanisms - September 27, 2020 Category: Biomedical Science Authors: Tromp, A. T., Zhao, Y., Jongerius, I., Heezius, E. C. J. M., Abrial, P., Ruyken, M., van Strijp, J. A. G., de Haas, C. J. C., Spaan, A. N., van Kessel, K. P. M., Henry, T., Haas, P.-J. A. Tags: Model Systems in Drug Discovery RESEARCH ARTICLE Source Type: research