The rise of antibiotic resistance poses an increasing threat to patients and presents a major challenge to healthcare systems worldwide. In this context, a multimodal approach is necessary, encompassing not only meticulous hygiene measures and a rational, responsible use of antibiotics but also the development of new therapeutic approaches. Given the limited progress in developing new antibiotics, it is prudent to explore novel approaches against bacterial pathogens. This may involve therapies based on antibodies or bacteriophages, as well as drugs designed to target bacterial virulence or host responses. Therefore, our research is focused to deepening our understanding of host-pathogen interactions, particularly emphasizing the human immune response to bacteria and the interplay of bacterial virulence factors with the host. Based on new insights into this intricate and dynamic interplay, our aim is to pioneer innovative immunotherapeutic approaches that target bacterial pathogens and amplify the host immune response to infections.
Antibodies that either inhibit secreted or cell-surface exposed virulence factors or trigger the antibacterial immune response of the host emerge as appealing alternatives or supplements to conventional antibiotics. Importantly, impeding virulence factors with antibodies functions independently from common antibiotic resistance mechanisms. Thus, it holds promise as a particularly effective strategy for treating severe infections caused by multi-drug resistant bacteria. Moreover, due to the extraordinarily long half-live of antibodies and excellent safety profiles, this approach may also encompass passive immunization strategies for individuals at an increased risk of severe infections, such as those undergoing chemotherapy or hematopoietic stem cell transplantation.
Over the past decade, multiple studies have highlighted the potential and effectiveness of patient-derived monoclonal antibodies (mAbs), primarily in the management and treatment of viral infections such as COVID-19, HIV, or Ebola Virus Disease. In these investigations, highly potent antibodies were discovered through extensive evaluation of antigen-responsive B cells sourced from individuals who were infected, recovered, or vaccinated. Despite the successful development of numerous antibodies targeting viral pathogens, only a limited number of mAb-based antibacterial approaches have been implemented in clinical care so far. Examples include antibodies that neutralize secreted toxins of Clostridioides difficile and mAbs designed for the prophylaxis and treatment of inhaled anthrax. However, the potential of patient-derived mAbs with the ability to neutralize bacterial virulence factors has not been thoroughly explored to date.
Recently we have focused on the development of patient-derived anti-PcrV antibodies targeting Pseudomonas aeruginosa (PA). PA 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 PA 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 PA and is composed of several proteins, including PcrV, a protein located at the tip of the T3SS. 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. By deciphering the B cell response to PcrV in a cohort of patients chronically infected with PA, we were able to produce numerous monoclonal anti-PcrV antibodies with highly neutralizing qualities against PA. In-depth mechanistic investigations, including cryogenic electron microscopy, pinpointed a surface-exposed C-terminal epitope on PcrV as the target for highly potent mAbs. These mAbs exhibited broad activity against drug-resistant PA strains. Importantly, their potency surpassed that of mouse-derived anti-PcrV mAbs and demonstrated effectiveness equivalent to conventional antibiotics in vivo.
To broaden our efforts in combating bacterial infections, we aim to adapt our approach to target other virulence factors of PA and other bacteria commonly associated with severe infections and the emergence of antimicrobial resistance. Therefore, we are working on establishing a comprehensive platform for developing monoclonal antibodies against bacterial virulence factors. This platform comprises various screening assays to identify individuals with antibacterial antibodies within a study cohort, followed by the characterization and production of patient-derived mAbs from specific B cells. The mode of action of these antibodies includes the direct inhibition of specific bacterial virulence factors or enhancing the immune response of the host. This approach enables us to identify and produce a multitude of diverse antibodies targeting various bacteria species, representing an almost limitless source of new antibodies, target epitopes, and therapeutic approaches. Monoclonal antibodies with proven protective effects are planned for further evaluation in clinical trials and are expected to serve as the foundation for potentially life-saving new therapeutics in the future - particularly for severe infections with MDR bacteria and as prophylactic treatment for immunocompromised patients.
The ultimate aim of our projects is to work towards the 'bench to bedside' concept, providing a foundation for the implementation of potentially lifesaving new therapeutics in clinical care for severe bacterial infections, including those caused by multidrug-resistant bacteria. In particular, we focus on:
