Human monoclonal antibodies targeting A35 protect from death caused by mpox

Raianna F Fantin¹, Meng Yuan², Seok-Chan Park³, Bailey Bozarth¹, Hallie Cohn¹, Maxinne Ignacio⁴, Patricia Earl⁴, Alesandro Civljak⁵, Gabriel Laghlali⁶, Ding Zhang², Xueyong Zhu², Jameson Crandell⁷, Valter Monteiro⁷, Jordan J Clark¹, Catherine Cotter⁴, Martin Burkhardt⁸, Gagandeep Singh⁵, Prajakta Warang³, Juan García-Bernalt Diego³, Komal Srivastava¹, Luz A Lugo⁹, Lauren Pischel¹⁰; PVI study group¹¹; Inci Yildirim¹², Saad B Omer¹³, Daniel da Silva¹⁴, Florian Krammer¹⁵, Goran Bajic⁵, Viviana Simon¹⁶, Michael Schotsaert¹⁷, Carolina Lucas¹⁸, Ian A Wilson¹⁹, Bernard Moss²⁰, Camila H Coelho²¹

Affiliations

¹ Department of Microbiology, Icahn School of Medicine at Mount Sinai, New York, NY, USA; Center for Vaccine Research and Pandemic Preparedness, Icahn School of Medicine at Mount Sinai, New York, NY, USA.
² Department of Integrative Structural and Computational Biology, The Scripps Research Institute, La Jolla, CA, USA.
³ Department of Microbiology, Icahn School of Medicine at Mount Sinai, New York, NY, USA; The Global Health and Emerging Pathogens Institute, Icahn School of Medicine at Mount Sinai, New York, NY, USA.
⁴ Laboratory of Viral Diseases, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, MD, USA.
⁵ Department of Microbiology, Icahn School of Medicine at Mount Sinai, New York, NY, USA.
⁶ Department of Microbiology, Icahn School of Medicine at Mount Sinai, New York, NY, USA; The Global Health and Emerging Pathogens Institute, Icahn School of Medicine at Mount Sinai, New York, NY, USA; Department of Pharmaceutics, Ghent University, Ghent, Belgium.
⁷ Department of Immunobiology, Yale School of Medicine, New Haven, CT, USA.
⁸ Recombinant Antibody and Antigen Development Unit, Laboratory of Malaria Immunology and Vaccinology, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, MD, USA.
⁹ Division of Infectious Diseases, Department of Medicine, Icahn School of Medicine at Mount Sinai, New York, NY, USA.
¹⁰ Section of Infectious Diseases, Department of Medicine, Yale School of Medicine, New Haven, CT, USA; Yale Institute for Global Health, Yale University, New Haven, CT, USA.
¹¹ Department of Microbiology, Icahn School of Medicine at Mount Sinai, New York, NY, USA; Center for Vaccine Research and Pandemic Preparedness, Icahn School of Medicine at Mount Sinai, New York, NY, USA; Department of Pathology, Molecular and Cell-Based Medicine, Icahn School of Medicine at Mount Sinai, New York, NY, USA.
¹² Department of Epidemiology of Microbial Diseases, Yale School of Public Health, New Haven, CT, USA; Yale Institute for Global Health, Yale University, New Haven, CT, USA; Department of Pediatrics, Section of Infectious Diseases and Global Health, Yale School of Medicine, New Haven, CT, USA; Center for Infection and Immunity, Yale University, New Haven, CT, USA.
¹³ Peter O'Donnell Jr. School of Public Health, University of Texas Southwestern Medical Center, Dallas, TX, USA.
¹⁴ Nash Family Department of Neuroscience, Icahn School of Medicine at Mount Sinai, New York, NY, USA.
¹⁵ Department of Microbiology, Icahn School of Medicine at Mount Sinai, New York, NY, USA; Center for Vaccine Research and Pandemic Preparedness, Icahn School of Medicine at Mount Sinai, New York, NY, USA; Department of Pathology, Molecular and Cell-Based Medicine, Icahn School of Medicine at Mount Sinai, New York, NY, USA; Ignaz Semmelweis Institute, Interuniversity Institute for Infection Research, Medical University of Vienna, Vienna, Austria.
¹⁶ Department of Microbiology, Icahn School of Medicine at Mount Sinai, New York, NY, USA; Center for Vaccine Research and Pandemic Preparedness, Icahn School of Medicine at Mount Sinai, New York, NY, USA; The Global Health and Emerging Pathogens Institute, Icahn School of Medicine at Mount Sinai, New York, NY, USA; Division of Infectious Diseases, Department of Medicine, Icahn School of Medicine at Mount Sinai, New York, NY, USA; Department of Pathology, Molecular and Cell-Based Medicine, Icahn School of Medicine at Mount Sinai, New York, NY, USA. Electronic address: viviana.simon@mssm.edu.
¹⁷ Department of Microbiology, Icahn School of Medicine at Mount Sinai, New York, NY, USA; The Global Health and Emerging Pathogens Institute, Icahn School of Medicine at Mount Sinai, New York, NY, USA; Precision Immunology Institute (PrIISM), Icahn School of Medicine at Mount Sinai, New York, NY, USA; Icahn Genomics Institute, Icahn School of Medicine at Mount Sinai, New York, NY, USA. Electronic address: michael.schotsaert@mssm.edu.
¹⁸ Department of Immunobiology, Yale School of Medicine, New Haven, CT, USA. Electronic address: carolina.lucas@yale.edu.
¹⁹ Department of Integrative Structural and Computational Biology, The Scripps Research Institute, La Jolla, CA, USA; The Skaggs Institute for Chemical Biology, The Scripps Research Institute, La Jolla, CA, USA. Electronic address: wilson@scripps.edu.
²⁰ Laboratory of Viral Diseases, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, MD, USA. Electronic address: bmoss@niaid.nih.gov.
²¹ Department of Microbiology, Icahn School of Medicine at Mount Sinai, New York, NY, USA; Center for Vaccine Research and Pandemic Preparedness, Icahn School of Medicine at Mount Sinai, New York, NY, USA; Precision Immunology Institute (PrIISM), Icahn School of Medicine at Mount Sinai, New York, NY, USA. Electronic address: camila.coelho@mssm.edu.

PMID: 40865529
DOI: 10.1016/j.cell.2025.08.004

Free article

Human monoclonal antibodies targeting A35 protect from death caused by mpox

Raianna F Fantin et al. Cell. 2025.

Free article

. 2025 Aug 26:S0092-8674(25)00918-3.

doi: 10.1016/j.cell.2025.08.004. Online ahead of print.

Authors

Affiliations

¹ Department of Microbiology, Icahn School of Medicine at Mount Sinai, New York, NY, USA; Center for Vaccine Research and Pandemic Preparedness, Icahn School of Medicine at Mount Sinai, New York, NY, USA.
² Department of Integrative Structural and Computational Biology, The Scripps Research Institute, La Jolla, CA, USA.
³ Department of Microbiology, Icahn School of Medicine at Mount Sinai, New York, NY, USA; The Global Health and Emerging Pathogens Institute, Icahn School of Medicine at Mount Sinai, New York, NY, USA.
⁴ Laboratory of Viral Diseases, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, MD, USA.
⁵ Department of Microbiology, Icahn School of Medicine at Mount Sinai, New York, NY, USA.
⁶ Department of Microbiology, Icahn School of Medicine at Mount Sinai, New York, NY, USA; The Global Health and Emerging Pathogens Institute, Icahn School of Medicine at Mount Sinai, New York, NY, USA; Department of Pharmaceutics, Ghent University, Ghent, Belgium.
⁷ Department of Immunobiology, Yale School of Medicine, New Haven, CT, USA.
⁸ Recombinant Antibody and Antigen Development Unit, Laboratory of Malaria Immunology and Vaccinology, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, MD, USA.
⁹ Division of Infectious Diseases, Department of Medicine, Icahn School of Medicine at Mount Sinai, New York, NY, USA.
¹⁰ Section of Infectious Diseases, Department of Medicine, Yale School of Medicine, New Haven, CT, USA; Yale Institute for Global Health, Yale University, New Haven, CT, USA.
¹¹ Department of Microbiology, Icahn School of Medicine at Mount Sinai, New York, NY, USA; Center for Vaccine Research and Pandemic Preparedness, Icahn School of Medicine at Mount Sinai, New York, NY, USA; Department of Pathology, Molecular and Cell-Based Medicine, Icahn School of Medicine at Mount Sinai, New York, NY, USA.
¹² Department of Epidemiology of Microbial Diseases, Yale School of Public Health, New Haven, CT, USA; Yale Institute for Global Health, Yale University, New Haven, CT, USA; Department of Pediatrics, Section of Infectious Diseases and Global Health, Yale School of Medicine, New Haven, CT, USA; Center for Infection and Immunity, Yale University, New Haven, CT, USA.
¹³ Peter O'Donnell Jr. School of Public Health, University of Texas Southwestern Medical Center, Dallas, TX, USA.
¹⁴ Nash Family Department of Neuroscience, Icahn School of Medicine at Mount Sinai, New York, NY, USA.
¹⁵ Department of Microbiology, Icahn School of Medicine at Mount Sinai, New York, NY, USA; Center for Vaccine Research and Pandemic Preparedness, Icahn School of Medicine at Mount Sinai, New York, NY, USA; Department of Pathology, Molecular and Cell-Based Medicine, Icahn School of Medicine at Mount Sinai, New York, NY, USA; Ignaz Semmelweis Institute, Interuniversity Institute for Infection Research, Medical University of Vienna, Vienna, Austria.
¹⁶ Department of Microbiology, Icahn School of Medicine at Mount Sinai, New York, NY, USA; Center for Vaccine Research and Pandemic Preparedness, Icahn School of Medicine at Mount Sinai, New York, NY, USA; The Global Health and Emerging Pathogens Institute, Icahn School of Medicine at Mount Sinai, New York, NY, USA; Division of Infectious Diseases, Department of Medicine, Icahn School of Medicine at Mount Sinai, New York, NY, USA; Department of Pathology, Molecular and Cell-Based Medicine, Icahn School of Medicine at Mount Sinai, New York, NY, USA. Electronic address: viviana.simon@mssm.edu.
¹⁷ Department of Microbiology, Icahn School of Medicine at Mount Sinai, New York, NY, USA; The Global Health and Emerging Pathogens Institute, Icahn School of Medicine at Mount Sinai, New York, NY, USA; Precision Immunology Institute (PrIISM), Icahn School of Medicine at Mount Sinai, New York, NY, USA; Icahn Genomics Institute, Icahn School of Medicine at Mount Sinai, New York, NY, USA. Electronic address: michael.schotsaert@mssm.edu.
¹⁸ Department of Immunobiology, Yale School of Medicine, New Haven, CT, USA. Electronic address: carolina.lucas@yale.edu.
¹⁹ Department of Integrative Structural and Computational Biology, The Scripps Research Institute, La Jolla, CA, USA; The Skaggs Institute for Chemical Biology, The Scripps Research Institute, La Jolla, CA, USA. Electronic address: wilson@scripps.edu.
²⁰ Laboratory of Viral Diseases, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, MD, USA. Electronic address: bmoss@niaid.nih.gov.
²¹ Department of Microbiology, Icahn School of Medicine at Mount Sinai, New York, NY, USA; Center for Vaccine Research and Pandemic Preparedness, Icahn School of Medicine at Mount Sinai, New York, NY, USA; Precision Immunology Institute (PrIISM), Icahn School of Medicine at Mount Sinai, New York, NY, USA. Electronic address: camila.coelho@mssm.edu.

PMID: 40865529
DOI: 10.1016/j.cell.2025.08.004

Abstract

The 2022 mpox outbreak highlighted the serious threat of monkeypox virus (MPXV), yet effective treatments are lacking. From an mpox-convalescent individual, we identified three high-affinity human monoclonal antibodies (mAbs) (named EV35-2, EV35-6, and EV35-7) that target the A35 protein in MPXV. These antibodies block viral spread in vitro and protect mice against lethal MPXV and vaccinia virus infection via both Fc-dependent and independent mechanisms. Levels of serum antibodies targeting the same epitopes are increased in mpox-convalescent humans, and higher levels of these antibodies in the sera are linked to shorter symptom duration and no hospitalization. Systems-level multivariate analysis indicated that mpox-convalescent serum antibodies targeting the same epitopic region as these three mAbs may function cooperatively, with additive associations to clinical protection. Two of the antibodies use a conserved IGHD2-21-encoded CxGGDCx motif in their CDRH3 region to bind a highly conserved poxvirus epitope. These findings establish A35 as a critical therapeutic target and highlight A35-specific mAbs as promising candidates for next-generation orthopoxvirus treatments.

Keywords: A35; MPXV; VACV; crystal structure; epitope; memory B cells; monoclonal antibodies; mpox; orthopoxvirus; therapy.

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Conflict of interest statement

Declaration of interests R.F.F., V.S., B.M., and C.H.C. are listed as inventors on a patent related to the monoclonal antibodies presented in this manuscript. The patent is titled “Antibodies and Antigen-Binding Fragments That Bind to Monkeypox Virus Protein A35 and Vaccinia Virus Protein A33, and Methods of Use” and is filed under U.S. serial number 63/723,296. The laboratory of M.S. has received unrelated funding support in sponsored research agreements from Phio Pharmaceuticals, 7 Hills Pharma, ArgenX BV, and Moderna.

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Human monoclonal antibodies targeting A35 protect from death caused by mpox

Affiliations

Human monoclonal antibodies targeting A35 protect from death caused by mpox

Authors

Affiliations

Abstract

Conflict of interest statement

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