Target-Agnostic Identification of Functional Monoclonal Antibodies Against Klebsiella pneumoniae Multimeric MrkA
Qun Wang1, Chew-Shun Chang2, Meghan Pennini1
1Department of Infectious Disease and Vaccines.
Abstract:
The increasing incidence of Klebsiella pneumoniae infections refractory to treatment with current broad-spectrum antibiotic classes warrants the exploration of alternative approaches, such as antibody therapy and/or vaccines, for prevention and treatment. However, the lack of validated targets shared by spectrums of clinical strains poses a significant challenge. We adopted a target-agnostic approach to identify protective antibodies against K. pneumoniae Several monoclonal antibodies were isolated from phage display and hybridoma platforms by functional screening for opsonophagocytic killing activity. We further identified their common target antigen to be MrkA, a major protein in the type III fimbriae complex, and showed that these serotype-independent anti-MrkA antibodies reduced biofilm formation in vitro and conferred protection in multiple murine pneumonia models. Importantly, mice immunized with purified MrkA proteins also showed reduced bacterial burden following K. pneumoniae challenge. Taken together, these results support MrkA as a promising target for K. pneumoniae antibody therapeutics and vaccines.
Insights
Antibody therapies targeting MrkA, a protein in Klebsiella pneumoniae type III fimbriae, show promise for treating infections. This serotype-independent approach reduced bacterial burden and biofilm formation in preclinical models.
Area of Science:
- Microbiology
- Immunology
- Infectious Diseases
Background:
- Rising antibiotic resistance in Klebsiella pneumoniae necessitates novel therapeutic strategies.
- Current treatment limitations highlight the need for alternative approaches like antibody therapy and vaccines.
- Identifying broadly protective targets against diverse K. pneumoniae strains is a significant challenge.
Purpose of the Study:
- To identify protective monoclonal antibodies against Klebsiella pneumoniae using a target-agnostic approach.
- To determine the specific antigen targeted by these protective antibodies.
- To evaluate the therapeutic potential of anti-MrkA antibodies and MrkA-based vaccines.
Main Methods:
- Phage display and hybridoma platforms were used to isolate monoclonal antibodies.
- Functional screening assessed opsonophagocytic killing activity.
- In vitro biofilm assays and murine pneumonia models were employed to evaluate efficacy.
- Immunization studies with purified MrkA protein were conducted in mice.
Main Results:
- Monoclonal antibodies targeting MrkA, a component of type III fimbriae, were identified.
- These antibodies demonstrated serotype-independent activity.
- Anti-MrkA antibodies reduced biofilm formation in vitro and protected mice in pneumonia models.
- Immunization with MrkA protein conferred protection against K. pneumoniae challenge.
Conclusions:
- MrkA is a promising, broadly applicable target for developing antibody therapeutics against Klebsiella pneumoniae.
- Anti-MrkA antibodies offer a potential strategy to combat antibiotic-resistant infections.
- MrkA-based vaccines could provide a novel preventative measure against K. pneumoniae.
