Prof. Martin Krönke, University Hospital Cologne; Dr Alexander Klimka, University Hospital Cologne
Staphylococcus aureus is a major human pathogen that causes a wide range of clinical infections like bacteremia and infective endocarditis as well as osteoarticular, skin and soft tissue, pleuropulmonary, and device-related infections. The morbidity and socioeconomic burden associated with infections with either methicillin-sensitive S. aureus (MSSA) or methicillin-resistant S. aureus (MRSA) define a clear unmet medical need. However, the pipelines are dry for new antibiotics and therefore, there is an urgent need for novel approaches, including vaccines.
We have developed, selected and secured IP for anti-pOxi D3 (StaphAcute), a S. aureus-specific humanized, monoclonal antibody (moAb) targeting protoporphyrinogen oxidase (pOxi) that is involved in heme synthesis, but has also been identified as an anchorless cell wall-associated protein. The anti-pOxi D3 antibody recognizes a protective epitope of pOxi that is conserved among > 95 % of S. aureus isolates. The importance of the selection process for protective epitopes by reverse immunology became obvious, as moAbs specific for a distinct epitope of the same S. aureus antigen lack protective efficacy. The direct acting, anti-proliferative mode-of-action is a distinctive feature of anti-pOxi D3.
After demonstration of safety, tolerability and efficacy of StaphAcute in clinical studies as an ideal adjunctive agent for the treatment of SAB in patients there would be a rationale to extend the range of indications for an anti S. aureus antibody towards severe pneumonia and surgical site infections. We are determined to taking the project under public funding to clinical proof-of-concept and to seek private (industry) partners then for licensing our product and continuation of clinical development and licensure.
We have demonstrated significant protective effects of the parental murine and the humanized anti-pOxi D3 as therapeutic, passive vaccine in an established mouse sepsis model. In addition, the cognate epitope of anti-pOxi D3, showed protection in mice when used as active vaccine.
Fraunhofer Institute for Toxicology and Experimental Medicine (FhG-ITEM) developed a process to manufacture StaphAcute as drug substance (DS). Funded by Deutsches Zentrum für Infektionsforschung (DZIF), a CHO-manufacturing cell line was optimized for high-level antibody expression and the manufacturing up-scale process was validated towards GMP quality attributes including virus validation, analytics and formulation of the antibody.
The patents EP2374467 A1 (pOxi), EP2374466 A1 (Triiso), EP000001987836B1 (hp2160) entitled “Protective staphylococcus aureus vaccine based on cell wall-associated proteins” have been granted in December 2011. The patent term runs until 2028. These patents secure these three antigens to be used. Concerning the protective epitopes a subsequent patent application has been filed (EP17156750.6; PCT/EP2018/053862).
StaphAcute will be used for additional pre-clinical studies to determine the efficacy of anti-pOxi D3 antibody in clinically relevant mouse osteomyelitis and respiratory infection models to extend the spectrum of medical indications for anti-pOxi D3 beyond SAB (S. aureus bacteremia).