PANTIPA: Monoclonal antibodies targeting Pseudomonas aeruginosa
Cryo-electron microscopic reconstruction of the antigen binding region of a human antibody (yellow) to the needle tip complex (blue) of the type III secretion system of Pseudomonas aeruginosa. Antibody binding results in the inhibition of the secretion system, which is a crucial virulence factor of P. aeruginosa.
Pseudomonas aeruginosa is a bacterial pathogen that can cause life-threatening infections, such as sepsis and pneumonia. One of the key weapons used by this bacterium is the type III secretion system (T3SS), which contains the protein PcrV. Researchers at the DZIF discovered that chronically infected patients develop highly effective antibodies against PcrV. Building on this finding, the researchers produced monoclonal antibodies (mAbs) that block the T3SS and neutralize P. aeruginosa's virulence. The PANTIPA project aims to develop a patient-derived monoclonal antibody for the treatment of severe P. aeruginosa infections. Following successful preclinical studies, UHC-D9b has been selected as the lead development candidate and is now entering the next stage of development, including process development and GMP-compliant manufacturing.
„With this project, we are laying the foundation for the transfer of innovative antibody therapies from basic research to clinical application. Our goal is to provide an effective and safe alternative for patients with severe infections.“
Background
Antibiotic resistance is one of the greatest challenges facing modern medicine. Pseudomonas aeruginosa is a particularly problematic pathogen that is often resistant to multiple conventional antibiotics, causing difficult-to-treat infections. It can cause life-threatening infections, such as pneumonia, wound infections, or sepsis, in severely ill or immunocompromised patients. The World Health Organization (WHO) considers P. aeruginosa one of the pathogens for which new treatment options must be developed urgently.
One particularly dangerous mechanism of P. aeruginosa is the type III secretion system (T3SS). This system enables the bacterium to inject toxic proteins directly into human cells, worsening the course of the disease. A central component of the T3SS is the protein PcrV, which acts as a "key" for the bacterium's attack. Blocking PcrV can inhibit the T3SS and thereby reduce the bacterium's virulence.
Development
Antibodies are natural components of the immune response that can recognize and neutralize specific pathogens or their components. DZIF researchers at the University Hospital Cologne have discovered that people infected with P. aeruginosa for an extended period produce highly effective antibodies against PcrV. Based on this finding, monoclonal antibodies (mAbs) that directly target PcrV were produced in the laboratory. In animal models, the antibodies reduced both bacterial burden and damage to lung tissue, with an efficacy comparable to that of conventional antibiotics.
During the first development phase, several antibody candidates were evaluated in preclinical studies. UHC-D9b emerged as the most promising candidate and was selected for further development.
In the second project phase, UHC-D9b is now being advanced towards clinical application. The antibody will be produced in cell cultures under strictly controlled Good Manufacturing Practice (GMP) conditions and tested against numerous clinical Pseudomonas isolates to assess its efficacy against different bacterial strains. In addition, the potential development of resistance to the antibody during treatment will be investigated. The Celonic Group has been selected as the specialized development partner for process development and GMP-compliant manufacturing.
At the same time, a comprehensive market analysis will assess potential applications from an economic perspective. This work will be carried out in close coordination with the DZIF's Product Development Unit, which is involved in project management.
The long-term goal is to develop UHC-D9b for two potential applications: the targeted treatment of acute P. aeruginosa infections, such as pneumonia or sepsis, and prophylactic use in particularly vulnerable patients through passive immunization.
PANTIPA and the further development of UHC-D9b are supported by several funding programmes:
- The research project (INNOPAK; Innovative Precision Antibodies Against Antibiotic-Resistant Pseudomonas aeruginosa Bacteria) is receiving €5.4 million in funding through the first funding round of the "GO-Bio next" program of the German Federal Ministry of Research, Technology and Space (BMFTR).
- ForTra gGmbH for Research Transfer (a subsidiary of Else Kröner-Fresenius Foundation (EKFS)) is providing €1.2 million to support the GMP-compliant production of the antibody.
- In addition, the EKFS is providing €350,000 through its "Translational Research" funding line to support the preparation of a Phase I trial, in which the antibody will be tested in humans for the first time.
