A humanized monoclonal antibody CgoX D3 recognizing coproporphyrinogen oxidase as therapeutic modality against S. aureus infection
Prof. Martin Krönke, University Hospital Cologne, Inst. Med. Microbiology; Dr Alexander Klimka, University Hospital Cologne, Inst. Med. Microbiology
S. aureus is a major human pathogen that causes a wide range of clinical infections including bacteremia, endocarditis, osteomyelitis or 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. Specifically, prophylactic or therapeutic vaccines are highly desirable for clinical management of S. aureus related diseases. Unfortunately, all previous S. aureus vaccine candidates failed in clinical trials. Although the medical as well as the commercial value of a S. aureus vaccine is undisputed, the negative perception of past vaccine developments represents a formidable challenge for new vaccine candidates.
We have identified, developed and characterized anti-CgoX D3, a S. aureus-specific humanized, monoclonal antibody (mAb) targeting coproporphyrinogen oxidase (CgoX, previously HemY) that is involved in heme synthesis, but has also been identified as an anchorless cell wall-associated protein. Anti-CgoX D3 is highly protective in murine sepsis models. The anti-CgoX D3 antibody recognizes a continuous 12 aa epitope of CgoX that is conserved by > 98 % within a selection of 33,000 clinical S. aureus isolates. Remarkably, the cognate D3 epitope proved highly protective when used for active immunization and suggests a unique potential for adjunctive treatment of invasive S. aureus infections like S. aureus bacteraemia (SAB).
The demonstration of safety, tolerability and efficacy of anti-CgoX D3 in clinical studies will qualify this vaccine candidate for clinical phase II trials, where anti-CgoX D3 will be tested as an adjunctive agent for the treatment of SAB patients. We are determined to de-risk the vaccine development by providing molecular knowledge about the mode of action, characterization of the serologic response in humans, and first-in-man studies using GMP-certified anti-CgoX D3.
We have demonstrated significant protective effects of the parental murine and the humanized anti-CgoX D3 as therapeutic, passive vaccine in an established mouse sepsis model. In addition, the cognate epitope of anti-CgoX D3, showed protection in mice when used as active vaccine as evidenced by significantly enhanced bacterial clearance and increased survival after S. aureus challenge. Fraunhofer Institute for Toxicology and Experimental Medicine developed a GMP process and manufactured anti-CgoX D3 as formulated drug product, which was funded by Deutsches Zentrum für Infektionsforschung (DZIF).
The patents EP2374467 A1 (CgoX), EP2374466 A1 (TPI), EP000001987836B1 (ABH2140 previously 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 i) for active immunization, ii) as target antigens for therapeutic antibodies (passive immunization), or iii) development of novel diagnostics and biomarkers. Concerning the protective, non-protective epitopes a subsequent patent application has been filed (world-wide PCT 3582807 and EP17156750.6 "Polypeptide epitopes of S. aureus and respective monoclonal antibodies for the treatment of infections and immune-diagnosis") to secure epitope-based intellectual property.
The preclinical characterization of anti-CgoX D3 has been described in a manuscript “Epitope-specific Immunity against Staphylococcus aureus Coproporphyrinogen III Oxidase” by A. Klimka et. al., which will be published in NPJ Vaccines.