Improvement of antibody functionality by structure-guided paratope engraftment

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, Anthony S. Fauci, Peter D. Kwong, John R. Mascola and Paolo Lusso ()
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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

Nature Communications, 2019, vol. 10, issue 1, 1-13

Abstract: 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.

Date: 2019
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DOI: 10.1038/s41467-019-08658-4

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