Molecular determinants of cross-reactivity and potency by VH3-33 antibodies against the Plasmodium falciparum circumsporozoite protein
Elaine Thai,
Rajagopal Murugan,
Špela Binter,
Clare Burn Aschner,
Katherine Prieto,
Audrey Kassardjian,
Anna S. Obraztsova,
Ryu Won Kang,
Yevel Flores-Garcia,
Shamika Mathis-Torres,
Kan Li,
Gillian Q. Horn,
Richard H.C. Huntwork,
Judith M. Bolscher,
Marloes H.C. de Bruijni,
Robert Sauerwein,
S. Moses Dennison,
Georgia D. Tomaras,
Fidel Zavala,
Paul Kellam,
Hedda Wardemann,
Jean-Philippe Julien
Affiliations
Elaine Thai
Program in Molecular Medicine, The Hospital for Sick Children Research Institute, Toronto, ON M5G 0A4, Canada; Department of Biochemistry, University of Toronto, Toronto, ON M5S 1A8, Canada
Rajagopal Murugan
B Cell Immunology, German Cancer Research Center (DKFZ), 69120 Heidelberg, Germany
Špela Binter
Kymab Ltd./Sanofi, The Bennet Building (B930), Babraham Research Campus, Cambridge CB22 3AT, UK; RQ Biotechnology Limited, 7th Floor Lynton House, 7–12 Tavistock Square, London WC1H 9LT, UK
Clare Burn Aschner
Program in Molecular Medicine, The Hospital for Sick Children Research Institute, Toronto, ON M5G 0A4, Canada
Katherine Prieto
Program in Molecular Medicine, The Hospital for Sick Children Research Institute, Toronto, ON M5G 0A4, Canada
Audrey Kassardjian
Program in Molecular Medicine, The Hospital for Sick Children Research Institute, Toronto, ON M5G 0A4, Canada; Department of Immunology, University of Toronto, Toronto, ON M5S 1A8, Canada
Anna S. Obraztsova
B Cell Immunology, German Cancer Research Center (DKFZ), 69120 Heidelberg, Germany; Biosciences Faculty, University of Heidelberg, 69117 Heidelberg, Germany
Ryu Won Kang
Program in Molecular Medicine, The Hospital for Sick Children Research Institute, Toronto, ON M5G 0A4, Canada; Department of Immunology, University of Toronto, Toronto, ON M5S 1A8, Canada
Yevel Flores-Garcia
Department of Molecular Microbiology and Immunology, Malaria Research Institute, Johns Hopkins Bloomberg School of Public Health, Baltimore, MD 21205, USA
Shamika Mathis-Torres
Department of Molecular Microbiology and Immunology, Malaria Research Institute, Johns Hopkins Bloomberg School of Public Health, Baltimore, MD 21205, USA
Kan Li
Departments of Surgery, Integrative Immunobiology, Molecular Genetics, and Microbiology, Center for Human Systems Immunology, Duke University, Durham, NC 27710, USA
Gillian Q. Horn
Departments of Surgery, Integrative Immunobiology, Molecular Genetics, and Microbiology, Center for Human Systems Immunology, Duke University, Durham, NC 27710, USA
Richard H.C. Huntwork
Departments of Surgery, Integrative Immunobiology, Molecular Genetics, and Microbiology, Center for Human Systems Immunology, Duke University, Durham, NC 27710, USA
Judith M. Bolscher
TropIQ Health Sciences, 6534 AT Nijmegen, the Netherlands
Marloes H.C. de Bruijni
TropIQ Health Sciences, 6534 AT Nijmegen, the Netherlands
Robert Sauerwein
TropIQ Health Sciences, 6534 AT Nijmegen, the Netherlands
S. Moses Dennison
Departments of Surgery, Integrative Immunobiology, Molecular Genetics, and Microbiology, Center for Human Systems Immunology, Duke University, Durham, NC 27710, USA
Georgia D. Tomaras
Departments of Surgery, Integrative Immunobiology, Molecular Genetics, and Microbiology, Center for Human Systems Immunology, Duke University, Durham, NC 27710, USA
Fidel Zavala
Department of Molecular Microbiology and Immunology, Malaria Research Institute, Johns Hopkins Bloomberg School of Public Health, Baltimore, MD 21205, USA
Paul Kellam
Kymab Ltd./Sanofi, The Bennet Building (B930), Babraham Research Campus, Cambridge CB22 3AT, UK; RQ Biotechnology Limited, 7th Floor Lynton House, 7–12 Tavistock Square, London WC1H 9LT, UK; Department of Infectious Diseases, Faculty of Medicine, Imperial College London, London SW7 2BX, UK
Hedda Wardemann
B Cell Immunology, German Cancer Research Center (DKFZ), 69120 Heidelberg, Germany; Corresponding author
Jean-Philippe Julien
Program in Molecular Medicine, The Hospital for Sick Children Research Institute, Toronto, ON M5G 0A4, Canada; Department of Biochemistry, University of Toronto, Toronto, ON M5S 1A8, Canada; Department of Immunology, University of Toronto, Toronto, ON M5S 1A8, Canada; Corresponding author
Summary: IGHV3-33-encoded antibodies are prevalent in the human humoral response against the Plasmodium falciparum circumsporozoite protein (PfCSP). Among VH3-33 antibodies, cross-reactivity between PfCSP major repeat (NANP), minor (NVDP), and junctional (NPDP) motifs is associated with high affinity and potent parasite inhibition. However, the molecular basis of antibody cross-reactivity and the relationship with efficacy remain unresolved. Here, we perform an extensive structure-function characterization of 12 VH3-33 anti-PfCSP monoclonal antibodies (mAbs) with varying degrees of cross-reactivity induced by immunization of mice expressing a human immunoglobulin gene repertoire. We identify residues in the antibody paratope that mediate cross-reactive binding and delineate four distinct epitope conformations induced by antibody binding, with one consistently associated with high protective efficacy and another that confers comparably potent inhibition of parasite liver invasion. Our data show a link between molecular features of cross-reactive VH3-33 mAb binding to PfCSP and mAb potency, relevant for the development of antibody-based interventions against malaria.
