DataVXAdvanced SciencePaper
journal article·2023-12Open access

Dendritic Cell‐Mediated Cross‐Priming by a Bispecific Neutralizing Antibody Boosts Cytotoxic T Cell Responses and Protects Mice against SARS‐CoV‐2

Rodrigo Lázaro‐Gorines, Patricia Pérez, Ignacio Heras‐Murillo, Irene Adán‐Barrientos, Guillermo Albericio, David Astorgano, Sara Flores, Joanna Luczkowiak, Nuria Labiod, Seandean L. Harwood, Alejandro Segura‐Tudela, Laura Rubio‐Pérez, Yudhi Nugraha, Xiaoran Shang, Yuxing Li, Carlos Alfonso, Kaylin A. Adipietro, Dinendra L. Abeyawardhane, Rocío Navarro, Marta Compte, Wenbo Yu, Alexander D. MacKerell, Laura Sanz, David J. Weber, Francisco J. Blanco, Mariano Esteban, Edwin Pozharski, Raquel Godoy‐Ruiz, Inés G. Muñoz, Rafael Delgado, David Sancho, Juan García‐Arriaza, Luis Álvarez‐Vallina

Advanced Science· Volume 10· Issue 34
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Source abstract

Abstract

Abstract Administration of neutralizing antibodies (nAbs) has proved to be effective by providing immediate protection against SARS‐CoV‐2. However, dual strategies combining virus neutralization and immune response stimulation to enhance specific cytotoxic T cell responses, such as dendritic cell (DC) cross‐priming, represent a promising field but have not yet been explored. Here, a broadly nAb, TNT, are first generated by grafting an anti‐RBD biparatopic tandem nanobody onto a trimerbody scaffold. Cryo‐EM data show that the TNT structure allows simultaneous binding to all six RBD epitopes, demonstrating a high‐avidity neutralizing interaction. Then, by C‐terminal fusion of an anti‐DNGR‐1 scFv to TNT, the bispecific trimerbody TNTDNGR‐1 is generated to target neutralized virions to type 1 conventional DCs (cDC1s) and promote T cell cross‐priming. Therapeutic administration of TNTDNGR‐1, but not TNT, protects K18‐hACE2 mice from a lethal SARS‐CoV‐2 infection, boosting virus‐specific humoral responses and CD8+ T cell responses. These results further strengthen the central role of interactions with immune cells in the virus‐neutralizing antibody activity and demonstrate the therapeutic potential of the Fc‐free strategy that can be used advantageously to provide both immediate and long‐term protection against SARS‐CoV‐2 and other viral infections.
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Research context

Nanomaterials

OpenAlex topics: SARS-CoV-2 and COVID-19 Research · Immunotherapy and Immune Responses · Monoclonal and Polyclonal Antibodies Research

SciVX discovery tags are terminology-based. OpenAlex topics are source-provided classifications.

Affiliations

Cancer Immunotherapy Unit (UNICA) Department of Immunology Hospital Universitario 12 de Octubre Madrid 28041 Spain

Immuno‐Oncology and Immunotherapy Group Instituto de Investigación Sanitaria 12 de Octubre (imas12) Madrid 28041 Spain

H12O‐CNIO Cancer Immunotherapy Clinical Research Unit Centro Nacional de Investigaciones Oncológicas (CNIO) Madrid 28029 Spain

Department of Molecular and Cellular Biology Centro Nacional de Biotecnología (CNB) Consejo Superior de Investigaciones Científicas (CSIC) Madrid 28049 Spain

Centro de Investigación Biomédica en Red de Enfermedades Infecciosas (CIBERINFEC) Madrid 28029 Spain

Immunobiology lab Centro Nacional de Investigaciones Cardiovasculares (CNIC) Madrid 28029 Spain

Virology and HIV/AIDS Group Instituto de Investigación Sanitaria 12 de Octubre (imas12) Madrid 28041 Spain

Department of Molecular Biology and Genetics – Protein Science Aarhus University Aarhus 80000 Denmark

Chair for Immunology UFV/Merck Universidad Francisco de Vitoria (UFV) Pozuelo de Alarcón Madrid 28223 Spain

Protein Crystallography Unit Structural Biology Programme Centro Nacional de Investigaciones Oncológicas (CNIO) Madrid 28029 Spain

Institute for Bioscience and Biotechnology Research University of Maryland Rockville MD 20850 USA

Department of Microbiology and Immunology University of Maryland School of Medicine Baltimore MD 21201 USA

The Center for Biomolecular Therapeutics Rockville MD 20850 USA

Centro de Investigaciones Biológicas Margarita Salas (CIB) Consejo Superior de Investigaciones Científicas (CSIC) Madrid 28040 Spain

Biochemistry and Molecular Biology University of Maryland School of Medicine Baltimore MD 21201 USA

Department of Antibody Engineering Leadartis SL Tres Cantos Madrid 28002 Spain

Computer Aided Drug Design Center Department of Pharmaceutical Sciences University of Maryland School of Pharmacy Baltimore MD 21201 USA

Center for Biomolecular Therapeutics (CBT) University of Maryland School of Medicine Baltimore MD 21201 USA

Molecular Immunology Unit Hospital Universitario Puerta de Hierro Majadahonda Majadahonda Madrid 28220 Spain

Department of Microbiology Hospital Universitario 12 de Octubre Madrid 28041 Spain

Department of Medicine Universidad Complutense de Madrid Madrid 28040 Spain

Funding

Fundación BBVA · Comunidad de Madrid · Horizon 2020 · 'la Caixa' Foundation · Instituto de Salud Carlos III · CRIS Cancer Foundation

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