Background Macrophage Migration Inhibitory Factor (MIF) is a pleiotropic inflammatory cytokine and a primary counter-regulator of glucocorticoids (GCs) that emerged as a pivotal regulator of chronic inflammation including inflammatory bowel diseases (IBD). MIF occurs in two immunologically distinct, conformational isoforms: reduced MIF, ubiquitously present in various tissues and the circulation of healthy subjects, and oxidized MIF (oxMIF), described as the pathogenic and druggable isoform of MIF. In this study we evaluated the anti-inflammatory effects of the anti-oxMIF antibody ON104 in two different mouse models of colitis. Methods The fully human antibody ON104, which specifically targets oxMIF, was generated by advanced antibody engineering technology. The therapeutic potential of the Fc-silenced ON104 antibody was tested in two different models of colitis in mice: the acute model of DSS-induced colitis in C57BL/6 mice and the chronic model of adoptive T-cell transfer in SCID mice. At disease induction, ON104 was given twice a week for 8 weeks (chronic colitis) or three times for 1 week (acute colitis). Body weight, stool consistency, and rectal bleeding were assessed to evaluate colitis severity. At the end of the DSS-induced colitis model, colons were dissected for immuno-histological examinations. Results ON104 antibody, specifically directed against oxMIF, was completely devoid of Fcγ receptors binding and cytokine triggering in the presence of immune cells. Treatment with ON104 in the chronic colitis model substantially attenuated clinical signs of colitis by thwarting body weight loss and restoring stool consistency. In the acute DSS colitis model, oxMIF neutralization was able to reduce mucosal thickness and colonic immune cell infiltration compared to vehicle-treated mice. Conclusion Our findings substantiate the role of oxMIF in the pathogenesis of experimental colitis. Thus, targeting oxMIF may represent a new and promising treatment option for IBD.

Background: T cell immunity is key for the control of viral infections including SARS-CoV-2, in particular with regard to immune memory and protection against arising genetic variants. Method: We recently evaluated a peptide-based SARS-CoV-2 T cell activator termed CoVac-1 in a first-in-human clinical trial and observed a favorable safety profile and induction of poly-specific T cell responses until month 3. Here, we report on long-term safety and efficacy data of CoVac-1 in healthy adults until month 12. Findings: CoVac-1 is well tolerated without long-term immune-related side effects and induces long-lasting anti-viral T cell responses in 100% of study participants. Potent expandability of CD4+ and CD8+ T cells targeting multiple different CoVac-1 T cell epitopes was observed 6 and 12 months after one single dose of CoVac-1. T cell responses were associated with the severity and the number of local adverse events at injection site. Beyond induction of T cell immunity, 89% of study participants developed CoVac-1-specific IgG antibody titers which associated with the intensity of the T cell response, indicating that CoVac-1-specific CD4+ T cells support the induction of B cell responses. Vaccination with approved COVID-19 vaccines boosted CoVac-1-specific T cell responses. Overall, a low SARS-CoV-2 infection rate was observed in the study population (8.3% of participants until month 12). Interpretation: Together, a single application of CoVac-1 elicits long-lived and broad SARS-CoV-2-specific T cell immunity, which further supports the current evaluation of our T cell activator in patients with congenital or acquired B cell defects (NCT04954469). Funding: This trial is funded by the Ministry of Science, Research and the Arts Baden-Wuerttemberg., Germany