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Improvement of antibody functionality by structure-guided paratope engraftment.
Liu, Qingbo; Lai, Yen-Ting; Zhang, Peng; Louder, Mark K; Pegu, Amarendra; Rawi, Reda; Asokan, Mangaiarkarasi; Chen, Xuejun; Shen, Chen-Hsiang; Chuang, Gwo-Yu; Yang, Eun Sung; Miao, Huiyi; Wang, Yuge; Fauci, Anthony S; Kwong, Peter D; Mascola, John R; Lusso, Paolo.
  • Liu Q; Laboratory of Immunoregulation, National Institute of Allergy and Infectious Diseases, NIH, Bethesda, MD, 20892, USA.
  • Lai YT; Vaccine Research Center, National Institute of Allergy and Infectious Diseases, NIH, Bethesda, MD, 20892, USA.
  • Zhang P; Laboratory of Immunoregulation, National Institute of Allergy and Infectious Diseases, NIH, Bethesda, MD, 20892, USA.
  • Louder MK; Vaccine Research Center, National Institute of Allergy and Infectious Diseases, NIH, Bethesda, MD, 20892, USA.
  • Pegu A; Vaccine Research Center, National Institute of Allergy and Infectious Diseases, NIH, Bethesda, MD, 20892, USA.
  • Rawi R; Vaccine Research Center, National Institute of Allergy and Infectious Diseases, NIH, Bethesda, MD, 20892, USA.
  • Asokan M; Vaccine Research Center, National Institute of Allergy and Infectious Diseases, NIH, Bethesda, MD, 20892, USA.
  • Chen X; Vaccine Research Center, National Institute of Allergy and Infectious Diseases, NIH, Bethesda, MD, 20892, USA.
  • Shen CH; Vaccine Research Center, National Institute of Allergy and Infectious Diseases, NIH, Bethesda, MD, 20892, USA.
  • Chuang GY; Vaccine Research Center, National Institute of Allergy and Infectious Diseases, NIH, Bethesda, MD, 20892, USA.
  • Yang ES; Vaccine Research Center, National Institute of Allergy and Infectious Diseases, NIH, Bethesda, MD, 20892, USA.
  • Miao H; Laboratory of Immunoregulation, National Institute of Allergy and Infectious Diseases, NIH, Bethesda, MD, 20892, USA.
  • Wang Y; Laboratory of Immunoregulation, National Institute of Allergy and Infectious Diseases, NIH, Bethesda, MD, 20892, USA.
  • Fauci AS; Laboratory of Immunoregulation, National Institute of Allergy and Infectious Diseases, NIH, Bethesda, MD, 20892, USA.
  • Kwong PD; Vaccine Research Center, National Institute of Allergy and Infectious Diseases, NIH, Bethesda, MD, 20892, USA.
  • Mascola JR; Vaccine Research Center, National Institute of Allergy and Infectious Diseases, NIH, Bethesda, MD, 20892, USA.
  • Lusso P; Laboratory of Immunoregulation, National Institute of Allergy and Infectious Diseases, NIH, Bethesda, MD, 20892, USA. plusso@niaid.nih.gov.
Nat Commun ; 10(1): 721, 2019 02 13.
Article en En | MEDLINE | ID: mdl-30760721
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.
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Texto completo: 1 Banco de datos: MEDLINE Asunto principal: Sitios de Unión de Anticuerpos / Infecciones por VIH / VIH-1 / Anticuerpos Neutralizantes Tipo de estudio: Prognostic_studies Límite: Animals / Female / Humans Idioma: En Año: 2019 Tipo del documento: Article
Texto completo
Imprimir
XML
PubMed Links
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Texto completo: 1 Banco de datos: MEDLINE Asunto principal: Sitios de Unión de Anticuerpos / Infecciones por VIH / VIH-1 / Anticuerpos Neutralizantes Tipo de estudio: Prognostic_studies Límite: Animals / Female / Humans Idioma: En Año: 2019 Tipo del documento: Article