Bacterial infections pose still a major threat to human health around the world, which is aggravated by the appearance and spread of antimicrobial resistances. To overcome the limited amount of new chemical substances with antibiotic activity, development of targeted therapies seems reasonable. While targeted therapeutics based on antibodies have achieved great success in cancer therapy and as shown recently, in the treatment of viral infections such as COVID-19 and HIV, the development and application of monoclonal antibodies (mAb) in treatment of bacterial infections is still in early stages of discovery.
The aim of our research group is to establish a comprehensive platform to develop monoclonal antibodies for the treatment of severe bacterial infections including infections with multidrug-resistant (MDR) isolates. This platform is composed of different screening assays to identify individuals with antibacterial antibodies among a study cohort, followed by the characterization and production of patient-derived monoclonal antibodies from specific B cells. Mode of action of these antibodies includes direct inhibition of specific bacterial virulence factors, enhancing opsonophagocytosis or activation of the complement cascade and subsequent bacteriolysis. This approach allows us to identify and to produce a multitude of diverse antibodies targeting various MDR bacteria and represents a nearly exhaustless source of new antibodies, target epitopes and therapeutic approaches. Monoclonal antibodies with proven protective effects are supposed to be further evaluated in clinical trials and will hopefully provide a basis for lifesaving new therapeutics for severe infections with MDR bacteria as well as prophylactic treatment for immunocompromised patients in the future.
As Proof-of-Concept of our approach we have focused on the development of patient-derived anti-PcrV antibodies targeting Pseudomonas aeruginosa. P. aeruginosa is a Gram-negative bacterium with high levels of intrinsic and extrinsic antibiotic resistance mechanisms and is a frequent cause of severe infections especially in critically ill and immunocompromised patients. Pathogenicity of P. aeruginosa is mediated by several virulence factors such as lipopolysaccharide, type 4 pili, and the type three secretion system (T3SS). The T3SS is located at the outer membrane of P. aeruginosa and is composed of several proteins, including the PcrV protein. As the T3SS has been linked with bacterial persistence, higher relapse rates and increased mortality in infected patients, the T3SS represents an excellent therapeutic target.
Interestingly, we were able to identify individuals with antibodies with high binding capacity and neutralizing characteristics to the PcrV protein in a large study cohort. By isolation of PcrV-specific B cells from donors with evidence of highly protective anti-PcrV antibodies, we performed in-depth analyses of the B cell receptor repertoire and were able to produce numerous monoclonal anti-PcrV antibodies with highly neutralizing qualities against P. aeruginosa. Based on the proven feasibility and effectiveness of our Proof-of-Concept study, we are planning to establish a comprehensive platform to develop monoclonal antibodies targeting several virulence factors of P. aeruginosa and other clinically relevant bacterial infections.
In contrast to the described inhibition of bacterial virulence factors, antibodies can induce a strong innate immune response including the activation of the complement cascade and an enhanced phagocytosis. Based on developed screening assay we are focusing on the identification of antibodies, which are highly effective to induce an innate immune response. These screening assays will be integrated into the envisaged platform to identify, characterize, and produce antibodies, that bind bacteria and can induce an innate immune response such as an enhanced opsonophagocytosis by macrophages or an activation of the complement cascade and subsequent bacteriolysis.
This project will provide a platform for the detection and production of a multitude of diverse antibodies targeting several bacterial pathogens. For future clinical application, the combination of antibodies targeting different virulence factors simultaneously or the modification of antibodies could enhance efficacy dramatically and will be addressed in our proposed studies.
Development of antibacterial antibodies could enable clinicians worldwide to augment their standard therapy against lifethreatening bacterial infections with a novel and potent therapy. Moreover, we are highly interested in molecular mechanisms of host-pathogen interactions and development of infection models, both key elements for revealing the pathogenesis of bacterial infections and for the development of new therapeutic approaches.
The ultimate aim of our projects will be to work towards the “bench to bedside” concept to provide a basis for the authorization of potentially lifesaving new therapeutics for severe bacterial infections:
Postdoc: Dr. rer. nat. Alexandra Albus
PhD student: application process pending
TA: Dmitriy Holzmann
MD student: Kristin Schmitt