Engineered antibodies bypass bacterial immune evasion to drive complement-mediated protection against lethal infections.

Authors

Youssif M Ali, Munehisa Yabuki, Chanuka H Arachchilage, Priyanka Khatri, Nicholas J Lynch, Sebastian Bruchmann, Aaron Weimann, Karen Brown, Rodrigo Andres Floto, Julian Parkhill, Vidmantas Petraitis, Ruta Petraitiene, Thomas J Walsh, David E Briles, Larry S MacDaniel, Heidi Utsugi, Galina Gragerova, Ayesha Misquith, Christiana Doulami, Gregory Demopulos, Wilhelm Schwaeble

Published in

Science translational medicine. Volume 18. Issue 854. Pages eadx4108. Jun 17, 2026. Epub Jun 17, 2026.

Abstract

The expanding global crisis of bacterial infections caused by antimicrobial-resistant pathogens has resulted in an urgent need for therapeutics. Previous efforts to target pathogen surface antigens with monoclonal antibodies (mAbs) have sought to activate the complement system, primarily through the antibody-dependent classical pathway. However, most mAbs have induced insufficient complement activation because pathogen evasion strategies disrupt the complex spatiotemporal requirements for activation of the classical pathway initiation complex C1. To address this, we developed a targeted complement activation therapy (T-CAT), which uses antibodies furnished with the enzymatic capability to initiate complement activation directly on the bacterial surface without involvement of the classical pathway initiation complex. We found that T-CAT mAbs directed against bacterial surface antigens can overcome the strategies that pathogens evolved to escape from classical pathway-mediated clearance by the immune system. We further demonstrated that T-CAT mAbs could safely and effectively be used to treat infectious disease in experimental murine models of sepsis and pneumonia caused by Klebsiella pneumoniae, Pseudomonas aeruginosa, Streptococcus pneumoniae, and Neisseria meningitidis. Together, these data highlight the potential for T-CAT as a next-generation mAb platform with broad applicability against diverse microbial species, including multidrug-resistant pathogens, without promoting drug resistance.

PMID:
42308332
Bibliographic data and abstract were imported from PubMed on 18 Jun 2026.

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