Krönke Lab - Antimicrobial therapeutic antibodies
The current work of the CMMC Senior Research Group Krönke aims at driving a therapeutic anti-Staphylococcus (S.) aureus antibody from preclinical characterization and GMP production through clinical development starting with a phase I/IIa clinical trial. In this framework, a new S. aureus virulence factor, coproporphyrinogen III oxidase (CgoX) was described killing phagocytes at the interface of eukaryotic and staphylococcal porphyrin metabolism. Together with Dr. Alexander Klimka, a monoclonal anti-CgoX-D3 has been previously identified protecting mice against S. aureus infection in vivo. We discovered intracellular neutralization of CgoX as mode of action of anti-CgoX-D3. The GMP production of anti-CgoX-D3 at Fraunhofer-ITEM, Braunschweig, yielded 230 g of GMP-compliant drug substance. A combined Phase I/IIa study to investigate the safety and pharmacokinetics of anti-CgoX-D3 (StaphAcute) in healthy volunteers and patients with S. aureus bacteremia was initiated in May 2023.
Funding
German Center of Infection Research (DZIF)
Federal Ministry of Education and Research (BMBF)
Center for Molecular Medicine Cologne (CMMC)
Medical Faculty, University of Cologne
Tosetti B, Ward B, Grumme D, Herb M, Schramm M, Utermöhlen O, Heukamp LC, Krönke M,Krut O. NOX2 deficiency permits sustained survival of S. aureus in macrophages and contributes to severity of infection. Front Immunol. 2021. Doi: 10.3389/fimm633629.
Klimka A, Mertins S, Nicolai AK, Rummler LM, Higgins PG, Günther SD, Tosetti B, Krönke M. Epitope-specific immunity against S. aureus coproporphyrinogen III oxidase. NPJ Vaccines; 2021; doi.org/10.1038/s41541-020-00268-2.
Günther SD, Fritsch M, Seeger JM, Schiffmann LM, Snipas SJ, Coutelle M, Kufer TA, Higgins PG, Hornung V, Bernardini ML, Höning S, Krönke M, Salvesen GS, Kashkar H. (2020) Cytosolic Gram-negative bacteria prevent apoptosis by inhibition of effector caspases through lipopolysaccharide. Nat. Microbiol. 5: 354.
Fritsch M, Günther SD, Schwarzer R, Albert MC, Schorn F, Werthenbach JP, Schiffmann LM, Stair N, Stocks H, Seeger JM, Lamkanfi M, Krönke M, Pasparakis M, Kashkar H. (2019) Caspase-8 is the molecular switch for apoptosis, necroptosis and pyroptosis. Nature. 575: 683.
Herb M, Gluschko A, Wiegmann K, Farid A, Wolf A, Utermöhlen O, Krut O, Krönke M., Schramm M. (2019) Mitochondrial reactive oxygen species regulate pro-inflammatory signaling vie disulfide linkage of NEMO. Sci Signaling 12: doi: 10.1126/scisignal.aar5926.
Gluschko A, Herb M, Wiegmann K, Krut O, Neiss WF, Utermöhlen O, Krönke M, Schramm M. (2018) The β2 Integrin Mac-1 Induces Protective LC3-Associated Phagocytosis of Listeria monocytogenes. Cell Host Microbe. 23:324.
Glowalla E, Tosetti B, Krönke M, Krut O. Proteomics-based identification of anchorless cell wall proteins as vaccine candidates against Staphylococcus aureus. Infect Immun. 2009. 77: 2719.
