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

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

doi:10.1126/scitranslmed.adx4108

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

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

Center for Discovery and Innovation

Hackensack Meridian School of Medicine

Research output: Contribution to journal › Article › peer-review

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.

Original language	English
Article number	eadx4108
Journal	Science translational medicine
Volume	18
Issue number	854
DOIs	https://doi.org/10.1126/scitranslmed.adx4108
State	Published - Jun 17 2026

ASJC Scopus subject areas

General Medicine

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Ali, Y. M., Yabuki, M., Arachchilage, C. H., Khatri, P., Lynch, N. J., Bruchmann, S., Weimann, A., Brown, K., Floto, R. A., Parkhill, J., Petraitis, V., Petraitiene, R., Walsh, T. J., Briles, D. E., Macdaniel, L. S., Utsugi, H., Gragerova, G., Misquith, A., Doulami, C., ... Schwaeble, W. (2026). Engineered antibodies bypass bacterial immune evasion to drive complement-mediated protection against lethal infections. Science translational medicine, 18(854), Article eadx4108. https://doi.org/10.1126/scitranslmed.adx4108

@article{7477c5020edb413fafb5e53d60e50308,

title = "Engineered antibodies bypass bacterial immune evasion to drive complement-mediated protection against lethal infections",

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.",

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

note = "Publisher Copyright: Copyright {\textcopyright} 2026 The Authors, some rights reserved; exclusive licensee American Association for the Advancement of Science. No claim to original U.S. Government Works",

year = "2026",

month = jun,

day = "17",

doi = "10.1126/scitranslmed.adx4108",

language = "English",

volume = "18",

journal = "Science translational medicine",

issn = "1946-6234",

publisher = "American Association for the Advancement of Science",

number = "854",

}

Ali, YM, Yabuki, M, Arachchilage, CH, Khatri, P, Lynch, NJ, Bruchmann, S, Weimann, A, Brown, K, Floto, RA, Parkhill, J, Petraitis, V, Petraitiene, R, Walsh, TJ, Briles, DE, Macdaniel, LS, Utsugi, H, Gragerova, G, Misquith, A, Doulami, C, Demopulos, G & Schwaeble, W 2026, 'Engineered antibodies bypass bacterial immune evasion to drive complement-mediated protection against lethal infections', Science translational medicine, vol. 18, no. 854, eadx4108. https://doi.org/10.1126/scitranslmed.adx4108

TY - JOUR

T1 - Engineered antibodies bypass bacterial immune evasion to drive complement-mediated protection against lethal infections

AU - Ali, Youssif M.

AU - Yabuki, Munehisa

AU - Arachchilage, Chanuka H.

AU - Khatri, Priyanka

AU - Lynch, Nicholas J.

AU - Bruchmann, Sebastian

AU - Weimann, Aaron

AU - Brown, Karen

AU - Floto, Rodrigo Andres

AU - Parkhill, Julian

AU - Petraitis, Vidmantas

AU - Petraitiene, Ruta

AU - Walsh, Thomas J.

AU - Briles, David E.

AU - Macdaniel, Larry S.

AU - Utsugi, Heidi

AU - Gragerova, Galina

AU - Misquith, Ayesha

AU - Doulami, Christiana

AU - Demopulos, Gregory

AU - Schwaeble, Wilhelm

PY - 2026/6/17

Y1 - 2026/6/17

N2 - 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.

AB - 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.

UR - https://www.scopus.com/pages/publications/105042644044

U2 - 10.1126/scitranslmed.adx4108

DO - 10.1126/scitranslmed.adx4108

M3 - Article

C2 - 42308332

SN - 1946-6234

VL - 18

JO - Science translational medicine

JF - Science translational medicine

IS - 854

M1 - eadx4108

ER -

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

Abstract

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