ORIGINAL RESEARCH article

Front. Immunol.

Sec. Vaccines and Molecular Therapeutics

Volume 16 - 2025 | doi: 10.3389/fimmu.2025.1618297

This article is part of the Research TopicNew Insights in Nucleic Acid Approaches for Vaccine and Biologic DeliveryView all 10 articles

Fc-modification of anti-PcrV gene-encoded antibodies modulates complementmediated killing of Pseudomonas aeruginosa

Provisionally accepted
Jillian EisenhauerJillian Eisenhauer1,2*Spencer DublinSpencer Dublin3Jihae ChoiJihae Choi2Abigail R TrachtmanAbigail R Trachtman2Jacqueline D ChuJacqueline D Chu2David Custodio-ZegarraDavid Custodio-Zegarra2Suman BhartiSuman Bharti2Bhavya BardwajBhavya Bardwaj2Shuangyi BaiShuangyi Bai4William Thomas WittWilliam Thomas Witt3Maria De La Paz GutierrezMaria De La Paz Gutierrez3Sarah MillerSarah Miller3Kaitlyn FlowersKaitlyn Flowers2Trevor R F SmithTrevor R F Smith5Bronwyn GunnBronwyn Gunn4Mariette BarbierMariette Barbier3Elizabeth ParzychElizabeth Parzych2David WeinerDavid Weiner2*Ami PatelAmi Patel2*
  • 1Perelman School of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania, United States
  • 2Vaccine and Immunotherapy Center, The Wistar Institute of Anatomy and Biology, Philadelphia, United States
  • 3Department of Microbiology, Immunology and Cell Biology, School of Medicine, West Virginia University, Morgantown, West Virginia, United States
  • 4Paul G. Allen School for Global Health, College of Veterinary Medicine, Washington State University, Pullman, Washington, United States
  • 5Inovio Pharmaceuticals (United States), Plymouth Meeting, Pennsylvania, United States

The final, formatted version of the article will be published soon.

Select one of your emails

You have multiple emails registered with Frontiers:

Notify me on publication

Please enter your email address:

If you already have an account, please login

You don't have a Frontiers account ? You can register here

Pseudomonas aeruginosa is a high priority multi-drug-resistant (MDR) bacterial pathogen with increasing resistance against broad-spectrum antibiotics. Multiple efforts are ongoing to develop anti-pseudomonal vaccines however achieving meaningful outcomes has been challenging in human clinical trials. Monoclonal antibodies (MAbs) are emerging as promising biologics for targeting P. aeruginosa infections and engineering strategies that bridge engagement with innate immune mechanisms like complement-mediated antibody dependent phagocytosis may be beneficial to improve bacterial clearance. We previously described both protection and long-term expression of synthetic DNA-encoded MAb (DMAb) expressing the anti-PcrV MAb V2L2-MD. Here, we show that modification of DMAb-V2L2-MD with an Fc-point mutation designed to enhance complement engagement demonstrates improved binding to C1q, C3 deposition, and improved opsonophagocytic killing. This Fc-modified DMAb reduced P. aeruginosa bacteria burden in lungs and nasal washes in a lethal acute murine intranasal infection model. These data highlight the importance of tailoring downstream antibody innate effector functions to improve clearance of difficult-to-treat bacteria like MDR P. aeruginosa.

Keywords: Pseudomonas aeruginosa, PcrV, complement system, DNA-encoded monoclonal antibody, type III secretion system

Received: 25 Apr 2025; Accepted: 09 Jul 2025.

Copyright: © 2025 Eisenhauer, Dublin, Choi, Trachtman, Chu, Custodio-Zegarra, Bharti, Bardwaj, Bai, Witt, De La Paz Gutierrez, Miller, Flowers, Smith, Gunn, Barbier, Parzych, Weiner and Patel. This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) or licensor are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms.

* Correspondence:
Jillian Eisenhauer, Perelman School of Medicine, University of Pennsylvania, Philadelphia, 19104, Pennsylvania, United States
David Weiner, Vaccine and Immunotherapy Center, The Wistar Institute of Anatomy and Biology, Philadelphia, United States
Ami Patel, Vaccine and Immunotherapy Center, The Wistar Institute of Anatomy and Biology, Philadelphia, United States

Disclaimer: All claims expressed in this article are solely those of the authors and do not necessarily represent those of their affiliated organizations, or those of the publisher, the editors and the reviewers. Any product that may be evaluated in this article or claim that may be made by its manufacturer is not guaranteed or endorsed by the publisher.

Supplementary Material