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Improvement of antibody functionality by structure-guided paratope engraftment

Author

Listed:
  • Qingbo Liu

    (National Institute of Allergy and Infectious Diseases, NIH)

  • Yen-Ting Lai

    (National Institute of Allergy and Infectious Diseases, NIH)

  • Peng Zhang

    (National Institute of Allergy and Infectious Diseases, NIH)

  • Mark K. Louder

    (National Institute of Allergy and Infectious Diseases, NIH)

  • Amarendra Pegu

    (National Institute of Allergy and Infectious Diseases, NIH)

  • Reda Rawi

    (National Institute of Allergy and Infectious Diseases, NIH)

  • Mangaiarkarasi Asokan

    (National Institute of Allergy and Infectious Diseases, NIH)

  • Xuejun Chen

    (National Institute of Allergy and Infectious Diseases, NIH)

  • Chen-Hsiang Shen

    (National Institute of Allergy and Infectious Diseases, NIH)

  • Gwo-Yu Chuang

    (National Institute of Allergy and Infectious Diseases, NIH)

  • Eun Sung Yang

    (National Institute of Allergy and Infectious Diseases, NIH)

  • Huiyi Miao

    (National Institute of Allergy and Infectious Diseases, NIH)

  • Yuge Wang

    (National Institute of Allergy and Infectious Diseases, NIH)

  • Anthony S. Fauci

    (National Institute of Allergy and Infectious Diseases, NIH)

  • Peter D. Kwong

    (National Institute of Allergy and Infectious Diseases, NIH)

  • John R. Mascola

    (National Institute of Allergy and Infectious Diseases, NIH)

  • Paolo Lusso

    (National Institute of Allergy and Infectious Diseases, NIH)

Abstract

Broadly neutralizing antibodies (bNAbs) represent a promising alternative to antiretroviral drugs for HIV-1 prevention and treatment. Selected antibodies to the CD4-binding site bolster envelope trimer binding via quaternary contacts. Here, we rationally engraft a new paratope, i.e., the extended heavy-chain framework region 3 (FR3) loop of VRC03, which mediates quaternary interaction, onto several potent bNAbs, enabling them to reach an adjacent gp120 protomer. The interactive quaternary surface is delineated by solving the crystal structure of two FR3 loop-chimeric antibodies. Chimerization enhances the neutralizing activity of several potent bNAbs against a majority of global HIV-1 strains. Compared to unmodified antibodies, chimeric antibodies display lower autoreactivity and prolonged in vivo half-life in huFcRn mice and rhesus macaques. Thus, paratope engraftment may be used to expand the epitope repertory of natural antibodies, improving their functionality for disease prevention and treatment.

Suggested Citation

  • Qingbo Liu & Yen-Ting Lai & Peng Zhang & Mark K. Louder & Amarendra Pegu & Reda Rawi & Mangaiarkarasi Asokan & Xuejun Chen & Chen-Hsiang Shen & Gwo-Yu Chuang & Eun Sung Yang & Huiyi Miao & Yuge Wang &, 2019. "Improvement of antibody functionality by structure-guided paratope engraftment," Nature Communications, Nature, vol. 10(1), pages 1-13, December.
    • Handle: RePEc:nat:natcom:v:10:y:2019:i:1:d:10.1038_s41467-019-08658-4
    DOI: 10.1038/s41467-019-08658-4
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    Cited by:

    1. Zhi Yang & Kim-Marie A. Dam & Michael D. Bridges & Magnus A. G. Hoffmann & Andrew T. DeLaitsch & Harry B. Gristick & Amelia Escolano & Rajeev Gautam & Malcolm A. Martin & Michel C. Nussenzweig & Wayne, 2022. "Neutralizing antibodies induced in immunized macaques recognize the CD4-binding site on an occluded-open HIV-1 envelope trimer," Nature Communications, Nature, vol. 13(1), pages 1-14, December.

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