Somatic hypermutation-mediated paratope flexibility improves the cross-reactivity of human malaria antibodies

bioRxiv (Cold Spring Harbor Laboratory)

Abstract

ABSTRACT The protective capacity of antibodies targeting circumsporozoite protein on sporozoites of the malaria parasite Plasmodium falciparum (PfCSP) is linked to high affinity and cross-reactivity with the PfCSP central repeat domain and N-terminal junction. However, the role of somatic hypermutation (SHM) in the development of such antibodies remains unclear. Here we define the contributions of SHM to the high affinity and strong repeat and N-junction cross-reactivity of the potent anti-PfCSP monoclonal antibody (mAb) 4493 and of similar antibodies with shared SHM and affinity maturation trajectories. Molecular dynamics simulations reveal that SHM reduces the flexibility of the unbound mAb 4493 but increases the flexibility of the antigen-bound complex, thereby lowering the entropic cost for antigen binding. Furthermore, we identify an inverse relation between antibody affinity and serum stability, which limits the protective capacity of these antibodies. Our study provides molecular level evidence for the different roles that the SHM process plays in increasing VH3-49+Vκ3-20 antibody affinity and cross-reactivity and demonstrates how antibody affinity maturation can negatively impact antibody stability and thereby function.

Authors 15

1. Rajagopal Murugan corresponding Aachen

   Leiden University · German Cancer Research Center · Leiden University Medical Center

   Affiliation as printed

   B Cell Immunology, German Cancer Research Center, Heidelberg, Germany

   Leiden University Center for Infectious Diseases, Leiden University Medical Center, Leiden, The Netherlands

2. Anton Hanke

   University of Geneva · SIB Swiss Institute of Bioinformatics · Heidelberg Institute for Theoretical Studies

   Affiliation as printed

   Institute of Pharmaceutical Sciences of Western Switzerland, University of Geneva, Geneva, Switzerland

   Molecular and Cellular Modeling Group, Heidelberg Institute for Theoretical Studies (HITS), Heidelberg, Germany

   School of Pharmaceutical Sciences, University of Geneva, Geneva Switzerland

   Swiss Institute of Bioinformatics, Geneva, Switzerland

3. Opeyemi Ernest Oludada

   German Cancer Research Center · Heidelberg University

   Affiliation as printed

   B Cell Immunology, German Cancer Research Center, Heidelberg, Germany

   Biosciences Faculty, Heidelberg University, Heidelberg, Germany

4. Giulia Costa

   Max Planck Institute for Infection Biology

   Affiliation as printed

   Vector Biology Unit, Max Planck Institute for Infection Biology, Berlin, Germany

5. Yevel Flores-García

   Johns Hopkins University

   Affiliation as printed

   Department of Molecular Microbiology and Immunology, Malaria Research Institute, Johns Hopkins Bloomberg School of Public Health, Baltimore, MD, USA

6. Ghulam Mustafa

   German Cancer Research Center

   Affiliation as printed

   B Cell Immunology, German Cancer Research Center, Heidelberg, Germany

7. Kan Li

   Duke University

   Affiliation as printed

   Departments of Surgery and Integrative Immunobiology, Center for Human Systems Immunology, Duke University, Durham, NC, USA

8. Richard H.C. Huntwork

   Duke University

   Affiliation as printed

   Departments of Surgery and Integrative Immunobiology, Center for Human Systems Immunology, Duke University, Durham, NC, USA

9. Gillian Q. Horn

   Duke University

   Affiliation as printed

   Departments of Surgery and Integrative Immunobiology, Center for Human Systems Immunology, Duke University, Durham, NC, USA

10. Georgia D. Tomaras

    Duke University

    Affiliation as printed

    Departments of Surgery and Integrative Immunobiology, Center for Human Systems Immunology, Duke University, Durham, NC, USA

11. Fidel P. Zavala

    Johns Hopkins University

    Affiliation as printed

    Department of Molecular Microbiology and Immunology, Malaria Research Institute, Johns Hopkins Bloomberg School of Public Health, Baltimore, MD, USA

12. Elena A. Levashina

    Max Planck Institute for Infection Biology

    Affiliation as printed

    Vector Biology Unit, Max Planck Institute for Infection Biology, Berlin, Germany

13. Randal R. Ketchem

    Evotec (United States)

    Affiliation as printed

    Just - Evotec Biologics Inc., Seattle, WA, USA

14. Rebecca C. Wade corresponding

    Heidelberg University · DKFZ-ZMBH Alliance · Heidelberg Institute for Theoretical Studies

    Affiliation as printed

    Center for Molecular Biology of Heidelberg University (ZMBH), DKFZ-ZMBH Alliance, Heidelberg University, Heidelberg, Germany

    Interdisciplinary Center for Scientific Computing (IWR), Heidelberg University, Heidelberg, Germany

    Molecular and Cellular Modeling Group, Heidelberg Institute for Theoretical Studies (HITS), Heidelberg, Germany

15. Hedda Wardemann corresponding

    German Cancer Research Center

    Affiliation as printed

    B Cell Immunology, German Cancer Research Center, Heidelberg, Germany