CD14 Blockade Modulates Macrophage-Mediated Immunological Injury in a Translational Model of Reperfused ST-Segment Elevation Myocardial Infarction

Aascha A D'Elia Nee Brown¹, Helen Kiriazis², Jason Bloom³, Jonathan Noonan⁴, Ian Hsu⁵, Gabriella E Farrugia⁵, Haoyun Fang⁶, Stephanie Jansen⁷, Natalia Carvajal⁸, Crisdion Krstevski⁵, Waled A Shihata⁹, Yow Keat Tham¹⁰, Angela Vais¹¹, Camilla Cohen¹¹, Adam C Parslow¹², Chad Johnson¹³, Anita C Thomas¹⁴, Malathi S I Dona⁵, Kyah Grigolon¹, Scott J Y Loh¹, Guy Krippner², David K Wright¹⁵, Bing H Wang¹⁶, Antonio Abbate¹⁷, Junedh Amrute¹⁸, Kory Lavine¹⁸, Mark W Appleby¹⁹, David Crowe¹⁹, Garry Redlich¹⁹, Brian W Ziegelaar¹⁹, Julie R McMullen²⁰, David W Greening²¹, Alexander R Pinto²², David M Kaye²³, Daniel G Donner²⁴

Affiliations

¹ Translational Cardiology Centre, Baker Heart and Diabetes Institute, Melbourne, Australia.
² Translational Cardiology Centre, Baker Heart and Diabetes Institute, Melbourne, Australia; Baker Department of Cardiometabolic Health, University of Melbourne, Melbourne, Australia.
³ Heart Failure Laboratory, Baker Heart and Diabetes Institute, Melbourne, Australia; Department of Cardiology, Alfred Hospital, Melbourne, Australia.
⁴ Baker Department of Cardiometabolic Health, University of Melbourne, Melbourne, Australia; Atherothrombosis and Vascular Laboratory, Baker Heart and Diabetes Institute, Melbourne, Australia; School of Translational Medicine, Monash University, Melbourne, Australia.
⁵ Cardiac Cellular Systems Laboratory, Baker Heart and Diabetes Institute, Melbourne, Australia.
⁶ Molecular Proteomics Laboratory, Baker Heart and Diabetes Institute, Melbourne, Australia.
⁷ Alfred Medical Research and Education Precinct Animal Services, Melbourne, Australia.
⁸ Monash Sequencing, Monash University, Melbourne, Australia.
⁹ Heart Failure Laboratory, Baker Heart and Diabetes Institute, Melbourne, Australia.
¹⁰ Baker Department of Cardiometabolic Health, University of Melbourne, Melbourne, Australia; School of Translational Medicine, Monash University, Melbourne, Australia; Cardiac Hypertrophy Laboratory, Baker Heart and Diabetes Institute, Melbourne, Australia; Baker Department of Cardiovascular Research, Translation and Implementation, La Trobe University, Melbourne, Victoria, Australia.
¹¹ Monash Histology, Monash University, Melbourne, Australia.
¹² Baker Department of Cardiometabolic Health, University of Melbourne, Melbourne, Australia; Baker Department of Cardiovascular Research, Translation and Implementation, La Trobe University, Melbourne, Victoria, Australia; Baker Institute Microscopy Platform, Baker Heart and Diabetes Institute, Melbourne, Australia.
¹³ Bioimaging Platform, La Trobe University, Melbourne, Australia.
¹⁴ Translational Cardiology Centre, Baker Heart and Diabetes Institute, Melbourne, Australia; Department of Cardiology, Alfred Hospital, Melbourne, Australia.
¹⁵ Department of Neuroscience, Monash University, Melbourne, Australia.
¹⁶ School of Translational Medicine, Monash University, Melbourne, Australia; Biomarker Discovery Laboratory, Baker Heart and Diabetes Institute, Melbourne, Australia.
¹⁷ Robert M. Berne Cardiovascular Research Center, University of Virginia, Charlottesville, Virginia, USA.
¹⁸ Departments of Medicine, Pathology and Immunology, and Developmental Biology, Washington University School of Medicine, St Louis, Missouri, USA.
¹⁹ Implicit Bioscience Ltd, Brisbane, Australia and Seattle, Washington, USA.
²⁰ Baker Department of Cardiometabolic Health, University of Melbourne, Melbourne, Australia; School of Translational Medicine, Monash University, Melbourne, Australia; Cardiac Hypertrophy Laboratory, Baker Heart and Diabetes Institute, Melbourne, Australia; Department of Physiology, Monash University, Melbourne, Australia.
²¹ Baker Department of Cardiometabolic Health, University of Melbourne, Melbourne, Australia; School of Translational Medicine, Monash University, Melbourne, Australia; Molecular Proteomics Laboratory, Baker Heart and Diabetes Institute, Melbourne, Australia; Baker Department of Cardiovascular Research, Translation and Implementation, La Trobe University, Melbourne, Victoria, Australia.
²² Baker Department of Cardiometabolic Health, University of Melbourne, Melbourne, Australia; School of Translational Medicine, Monash University, Melbourne, Australia; Cardiac Cellular Systems Laboratory, Baker Heart and Diabetes Institute, Melbourne, Australia; Baker Department of Cardiovascular Research, Translation and Implementation, La Trobe University, Melbourne, Victoria, Australia.
²³ Heart Failure Laboratory, Baker Heart and Diabetes Institute, Melbourne, Australia; Department of Cardiology, Alfred Hospital, Melbourne, Australia; School of Translational Medicine, Monash University, Melbourne, Australia. Electronic address: david.kaye@baker.edu.au.
²⁴ Translational Cardiology Centre, Baker Heart and Diabetes Institute, Melbourne, Australia; Baker Department of Cardiometabolic Health, University of Melbourne, Melbourne, Australia; Department of Cardiology, Alfred Hospital, Melbourne, Australia; School of Translational Medicine, Monash University, Melbourne, Australia. Electronic address: daniel.donner@baker.edu.au.

PMID: 41134248
DOI: 10.1016/j.jacbts.2025.101393

Free article

CD14 Blockade Modulates Macrophage-Mediated Immunological Injury in a Translational Model of Reperfused ST-Segment Elevation Myocardial Infarction

Aascha A D'Elia Nee Brown et al. JACC Basic Transl Sci. 2025.

Free article

. 2025 Oct 14:101393.

doi: 10.1016/j.jacbts.2025.101393. Online ahead of print.

Authors

Affiliations

¹ Translational Cardiology Centre, Baker Heart and Diabetes Institute, Melbourne, Australia.
² Translational Cardiology Centre, Baker Heart and Diabetes Institute, Melbourne, Australia; Baker Department of Cardiometabolic Health, University of Melbourne, Melbourne, Australia.
³ Heart Failure Laboratory, Baker Heart and Diabetes Institute, Melbourne, Australia; Department of Cardiology, Alfred Hospital, Melbourne, Australia.
⁴ Baker Department of Cardiometabolic Health, University of Melbourne, Melbourne, Australia; Atherothrombosis and Vascular Laboratory, Baker Heart and Diabetes Institute, Melbourne, Australia; School of Translational Medicine, Monash University, Melbourne, Australia.
⁵ Cardiac Cellular Systems Laboratory, Baker Heart and Diabetes Institute, Melbourne, Australia.
⁶ Molecular Proteomics Laboratory, Baker Heart and Diabetes Institute, Melbourne, Australia.
⁷ Alfred Medical Research and Education Precinct Animal Services, Melbourne, Australia.
⁸ Monash Sequencing, Monash University, Melbourne, Australia.
⁹ Heart Failure Laboratory, Baker Heart and Diabetes Institute, Melbourne, Australia.
¹⁰ Baker Department of Cardiometabolic Health, University of Melbourne, Melbourne, Australia; School of Translational Medicine, Monash University, Melbourne, Australia; Cardiac Hypertrophy Laboratory, Baker Heart and Diabetes Institute, Melbourne, Australia; Baker Department of Cardiovascular Research, Translation and Implementation, La Trobe University, Melbourne, Victoria, Australia.
¹¹ Monash Histology, Monash University, Melbourne, Australia.
¹² Baker Department of Cardiometabolic Health, University of Melbourne, Melbourne, Australia; Baker Department of Cardiovascular Research, Translation and Implementation, La Trobe University, Melbourne, Victoria, Australia; Baker Institute Microscopy Platform, Baker Heart and Diabetes Institute, Melbourne, Australia.
¹³ Bioimaging Platform, La Trobe University, Melbourne, Australia.
¹⁴ Translational Cardiology Centre, Baker Heart and Diabetes Institute, Melbourne, Australia; Department of Cardiology, Alfred Hospital, Melbourne, Australia.
¹⁵ Department of Neuroscience, Monash University, Melbourne, Australia.
¹⁶ School of Translational Medicine, Monash University, Melbourne, Australia; Biomarker Discovery Laboratory, Baker Heart and Diabetes Institute, Melbourne, Australia.
¹⁷ Robert M. Berne Cardiovascular Research Center, University of Virginia, Charlottesville, Virginia, USA.
¹⁸ Departments of Medicine, Pathology and Immunology, and Developmental Biology, Washington University School of Medicine, St Louis, Missouri, USA.
¹⁹ Implicit Bioscience Ltd, Brisbane, Australia and Seattle, Washington, USA.
²⁰ Baker Department of Cardiometabolic Health, University of Melbourne, Melbourne, Australia; School of Translational Medicine, Monash University, Melbourne, Australia; Cardiac Hypertrophy Laboratory, Baker Heart and Diabetes Institute, Melbourne, Australia; Department of Physiology, Monash University, Melbourne, Australia.
²¹ Baker Department of Cardiometabolic Health, University of Melbourne, Melbourne, Australia; School of Translational Medicine, Monash University, Melbourne, Australia; Molecular Proteomics Laboratory, Baker Heart and Diabetes Institute, Melbourne, Australia; Baker Department of Cardiovascular Research, Translation and Implementation, La Trobe University, Melbourne, Victoria, Australia.
²² Baker Department of Cardiometabolic Health, University of Melbourne, Melbourne, Australia; School of Translational Medicine, Monash University, Melbourne, Australia; Cardiac Cellular Systems Laboratory, Baker Heart and Diabetes Institute, Melbourne, Australia; Baker Department of Cardiovascular Research, Translation and Implementation, La Trobe University, Melbourne, Victoria, Australia.
²³ Heart Failure Laboratory, Baker Heart and Diabetes Institute, Melbourne, Australia; Department of Cardiology, Alfred Hospital, Melbourne, Australia; School of Translational Medicine, Monash University, Melbourne, Australia. Electronic address: david.kaye@baker.edu.au.
²⁴ Translational Cardiology Centre, Baker Heart and Diabetes Institute, Melbourne, Australia; Baker Department of Cardiometabolic Health, University of Melbourne, Melbourne, Australia; Department of Cardiology, Alfred Hospital, Melbourne, Australia; School of Translational Medicine, Monash University, Melbourne, Australia. Electronic address: daniel.donner@baker.edu.au.

PMID: 41134248
DOI: 10.1016/j.jacbts.2025.101393

Abstract

These preclinical trials provide the first evidence of cluster of differentiation 14 (CD14) blockade with a murine analogue of atibuclimab, a CD14-neutralizing antibody, preventing secondary immunological exacerbation of cardiac injury in a translational mouse model of reperfused ST-segment elevation myocardial infarction (STEMI), assessed using multiple clinical modalities. Multiomic studies suggest CD14 blockade downregulated macrophage-specific proinflammatory and tissue-wide remodeling processes without suppression of monocyte-macrophage infiltration or repair. These findings support a clinically practicable targeted immunomodulatory strategy of CD14 blockade initiated at reperfusion to prevent chronic immunological progression toward ischemic heart failure, and provide new insights into the pleiotropic roles of CD14 in inflammation and myocardial injury.

Keywords: CD14; antibody therapy; heart failure; immunomodulation; myocardial infarction.

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Conflict of interest statement

Funding Support and Author Disclosures This trial was sponsored by Implicit Bioscience Ltd, which provided contract research funds and materials (anti-CD14 antibody) with untethered scientific freedom. Support was also provided by the National Health and Medical Research Council and National Heart Foundation (postgraduate scholarships to Dr Bloom), National Health and Medical Research Council (fellowship to Drs Wright and Kaye), Shine On Foundation (Senior Research Fellowship to Dr Donner), Victorian Government Operational Infrastructure Support Program, and the Rebecca L. Cooper Medical Research Foundation. Dr Abbate has received research support from Implicit Bioscience Ltd. Drs Appleby, Crowe, Redlich, and Ziegelaar are employees of the trial sponsor (Implicit Bioscience Ltd), which maintains a commercial interest in the anti-CD14 monoclonal antibody, Atibuclimab (IC14). Drs Redlich and Ziegelaar are named inventors on patent WO2022051814A1 relating to the use of CD14 antagonist antibodies for treating myocardial infarction. All primary trial data was recorded, analyzed, and reported while blinded by the Baker Heart and Diabetes Institute and the study director (Dr Donner), independently of Implicit Bioscience Ltd. All other authors have reported that they have no relationships relevant to the contents of this paper to disclose.

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CD14 Blockade Modulates Macrophage-Mediated Immunological Injury in a Translational Model of Reperfused ST-Segment Elevation Myocardial Infarction

Affiliations

CD14 Blockade Modulates Macrophage-Mediated Immunological Injury in a Translational Model of Reperfused ST-Segment Elevation Myocardial Infarction

Authors

Affiliations

Abstract

Conflict of interest statement

LinkOut - more resources

Full Text Sources

Research Materials