iScience (Jul 2025)
In silico improvement of affinity for highly protective anti-malarial antibodies
- Mateo Reveiz,
- Prabhanshu Tripathi,
- Lais Da Silva Pereira,
- Patience Kerubo Kiyuka,
- Tracy Liu,
- Yongping Yang,
- Baoshan Zhang,
- Dorra Benmohamed,
- Brian G. Bonilla,
- Carl W. Carruthers, Jr.,
- Marlon Dillon,
- Daniel Gowetski,
- Sven Kratochvil,
- Gabriella Lagos,
- Mariah Lofgren,
- Ivan Loukinov,
- Shamika Mathis-Torres,
- Andrew J. Schaub,
- Elizabeth Scheideman,
- Arne Schön,
- Chen-Hsiang Shen,
- Yevel Flores-Garcia,
- Fidel Zavala,
- Facundo D. Batista,
- Azza H. Idris,
- Robert A. Seder,
- Peter D. Kwong,
- Reda Rawi
Affiliations
- Mateo Reveiz
- Vaccine Research Center, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, MD, USA
- Prabhanshu Tripathi
- Vaccine Research Center, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, MD, USA
- Lais Da Silva Pereira
- Vaccine Research Center, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, MD, USA
- Patience Kerubo Kiyuka
- Vaccine Research Center, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, MD, USA; Kenya Medical Research Institute, Centre for Geographic Medicine Research Coast, P.O. Box 230-80108, Kilifi, Kenya
- Tracy Liu
- Vaccine Research Center, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, MD, USA
- Yongping Yang
- Vaccine Research Center, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, MD, USA
- Baoshan Zhang
- Vaccine Research Center, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, MD, USA
- Dorra Benmohamed
- Vaccine Research Center, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, MD, USA
- Brian G. Bonilla
- Vaccine Research Center, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, MD, USA
- Carl W. Carruthers, Jr.
- Vaccine Research Center, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, MD, USA
- Marlon Dillon
- Vaccine Research Center, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, MD, USA
- Daniel Gowetski
- Vaccine Research Center, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, MD, USA
- Sven Kratochvil
- The Ragon Institute of Massachusetts General Hospital, Massachusetts Institute of Technology and Harvard University, Cambridge, MA, USA
- Gabriella Lagos
- Vaccine Research Center, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, MD, USA
- Mariah Lofgren
- Vaccine Research Center, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, MD, USA
- Ivan Loukinov
- Vaccine Research Center, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, MD, USA
- Shamika Mathis-Torres
- Malaria Research Institute, Johns Hopkins Bloomberg School of Public Health, Baltimore, MD 21205, USA
- Andrew J. Schaub
- Vaccine Research Center, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, MD, USA
- Elizabeth Scheideman
- Vaccine Research Center, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, MD, USA
- Arne Schön
- Department of Biology, Johns Hopkins University, Baltimore, MD, USA
- Chen-Hsiang Shen
- Vaccine Research Center, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, MD, USA
- Yevel Flores-Garcia
- Malaria Research Institute, Johns Hopkins Bloomberg School of Public Health, Baltimore, MD 21205, USA
- Fidel Zavala
- Malaria Research Institute, Johns Hopkins Bloomberg School of Public Health, Baltimore, MD 21205, USA
- Facundo D. Batista
- The Ragon Institute of Massachusetts General Hospital, Massachusetts Institute of Technology and Harvard University, Cambridge, MA, USA; Department of Immunology, Harvard Medical School, Boston, MA, USA; Department of Microbiology, Harvard Medical School, Boston, MA, USA; Department of Biology, Massachusetts Institute of Technology, Cambridge, MA, USA
- Azza H. Idris
- Vaccine Research Center, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, MD, USA; The Ragon Institute of Massachusetts General Hospital, Massachusetts Institute of Technology and Harvard University, Cambridge, MA, USA
- Robert A. Seder
- Vaccine Research Center, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, MD, USA; Corresponding author
- Peter D. Kwong
- Vaccine Research Center, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, MD, USA; Aaron Diamond AIDS Research Center, Columbia University Vagelos College of Physicians and Surgeons, New York, NY 10032, USA; Department of Biochemistry and Molecular Biophysics, Columbia University, New York, NY 10032, USA; Corresponding author
- Reda Rawi
- Vaccine Research Center, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, MD, USA; Corresponding author
- DOI
- https://doi.org/10.1016/j.isci.2025.112903
- Journal volume & issue
-
Vol. 28,
no. 7
p. 112903
Abstract
Summary: The monoclonal antibody CIS43 preferentially binds the junctional region of Plasmodium falciparum circumsporozoite protein (PfCSP) and is highly protective in humans. Here, we develop an in silico pipeline to improve antigen-antibody interaction energies and apply it to CIS43 variants elicited in CIS43-germline knock-in mice. Improved binding of CIS43 variants to the CIS43 junctional epitope (PfCSP peptide 21) was achieved by introducing single and double amino acid substitutions in the peptide 21-proximal heavy- and light-chain-variable regions. The best in silico designed variant, antibody P3-43-LS, was 2- to 3-fold more protective than antibody CIS43-LS, the clinical version of CIS43 with half-life extending leucine-serine (LS) mutations, and had comparable protection to the current best-in-class antibody (iGL-CIS43.D3-LS) to this region. Crystal structures of the improved antibodies revealed atomic-level interactions accounting for gains in binding affinity. This in silico approach to improve antibody affinity can thus be used to enhance potency of PfCSP monoclonal antibodies.
Keywords
