Simonis, Alexander - assoc. JRG 09 and CAP 27

The increasing prevalence of antimicrobial resistance poses a critical and escalating threat to patient health and presents substantial challenges to healthcare systems worldwide. Addressing this issue requires a multimodal strategy that includes not only stringent hygiene protocols and judicious antibiotic stewardship but also the pursuit of novel therapeutic strategies. To counter the shortage of novel anti-infectives, a paradigm shift in antimicrobial therapy is imperative, similar to innovations in oncology that have transitioned from non-specific chemotherapies to targeted immune-modulating treatments.

Our research seeks to expand the scope of therapeutic options by investigating novel approaches to target AMR-related infections. Central to our efforts is an investigation into host-pathogen interactions, particularly the complex dynamics between the human immune system and bacterial pathogens. By leveraging insights from these intricate interactions, we aim to develop innovative immunotherapeutic strategies that not only target bacterial pathogens directly but also potentiate the host immune response to combat infections more effectively. This approach holds promise for addressing the urgent need for effective treatment options against multidrug-resistant bacterial infections.

Targeting bacterial virulence factors by monoclonal antibodies

Antibodies that either inhibit secreted or cell-surface-exposed virulence factors or activate the host’s antibacterial immune response are emerging as promising alternatives or supplements to conventional antibiotics. Importantly, targeting virulence factors with antibodies functions independently of common antibiotic resistance mechanisms, offering a particularly effective strategy for treating severe infections caused by multidrug-resistant bacteria. Moreover, due to the exceptionally long half-life and favorable safety profile of antibodies, this approach could also support passive immunization strategies for individuals at high risk of severe infections, such as those undergoing chemotherapy or hematopoietic stem cell transplantation.

Our recent research has focused on developing patient-derived anti-PcrV antibodies targeting Pseudomonas aeruginosa (PA). PA is a Gram-negative bacterium with extensive intrinsic and extrinsic antibiotic resistance mechanisms and frequently causes severe infections, particularly in critically ill and immunocompromised patients. PA pathogenicity is driven by several virulence factors, including lipopolysaccharide, type IV pili, and the type III secretion system (T3SS). The T3SS, located on the outer membrane of PA, comprises multiple proteins, including PcrV, a protein positioned at the tip of the T3SS. Given its association with bacterial persistence, higher relapse rates, and increased mortality in infected patients, the T3SS is an ideal therapeutic target. By investigating the B cell response to PcrV in a cohort of chronically infected PA patients, we successfully generated numerous monoclonal anti-PcrV antibodies exhibiting potent neutralizing effects against PA. In-depth mechanistic studies, including cryogenic electron microscopy, identified a surface-exposed C-terminal epitope on PcrV as the target for these highly potent monoclonal antibodies (mAbs). These mAbs demonstrated broad activity against drug-resistant PA strains, with efficacy surpassing that of mouse-derived anti-PcrV mAbs and showing in vivo effectiveness comparable to conventional antibiotics.

To further expand our efforts in combating bacterial infections, we aim to adapt this approach to target additional PA virulence factors and other bacteria commonly implicated in severe infections and antimicrobial resistance. Accordingly, we are developing a comprehensive platform for generating monoclonal antibodies against bacterial virulence factors. This platform includes various screening assays to identify individuals within a study cohort who possess antibacterial antibodies, followed by the characterization and production of patient-derived mAbs from specific B cells. The mode of action of these antibodies involves either direct inhibition of bacterial virulence factors or enhancement of the host immune response. This approach allows us to identify and produce a diverse array of antibodies targeting multiple bacterial species, providing an extensive source of new antibodies, target epitopes, and therapeutic options. Monoclonal antibodies with demonstrated protective effects are slated for further evaluation in clinical trials and hold potential as foundational, life-saving therapies, especially for treating severe infections with multidrug-resistant bacteria and as prophylactic treatments for immunocompromised patients.

The aim of our research group is to establish a comprehensive platform to develop novel antibody-based therapeutic approaches for the treatment of severe bacterial infections including infections with multidrug-resistant isolates. 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 life-threatening bacterial infections with a novel and potent therapy.

Our aims and further perspectives

The ultimate aim of our projects is to advance the 'bench to bedside' concept, establishing a foundation for the implementation of potentially lifesaving therapeutics in clinical care for severe bacterial infections, including those caused by multidrug-resistant organisms. Specifically, we focus on:

• Gaining new insights into host-pathogen interactions in bacterial infections through comprehensive analyses of both the adaptive and innate immune responses.
• Exploring novel treatment strategies targeting a range of clinically significant bacteria, with a strong emphasis on antibody-based therapies.
• Modulating the human immune response for the treatment of severe bacterial infections.
• Developing and refining infection models to enhance our understanding of pathogenic processes.
• Advancing translational projects into early clinical trials to evaluate the efficacy and safety of new therapeutic approaches.

For more information, please check Simonis Lab. 

• German Center for Infection Research (DZIF), Partner Site Bonn-Cologne, Cologne, Germany
• Center for Molecular Medicine Cologne (CMMC), Faculty of Medicine and University Hospital Cologne, University of Cologne
• Translational Research Unit – Infectious Diseases (TRU-ID), Department I of Internal Medicine, Faculty of Medicine and University Hospital Cologne, University of Cologne
• Department I of Internal Medicine, Faculty of Medicine and University Hospital Cologne, University of Cologne