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Improving the efficacy of plant-made anti-HIV monoclonal antibodies for clinical use.
Grandits, Melanie; Grünwald-Gruber, Clemens; Gastine, Silke; Standing, Joseph F; Reljic, Rajko; Teh, Audrey Y-H; Ma, Julian K-C.
Afiliación
  • Grandits M; Molecular Immunology Unit, Institute for Infection and Immunity, St. George's University of London, London, United Kingdom.
  • Grünwald-Gruber C; Core Facility Mass Spectrometry, University of Natural Resources and Life Sciences, Vienna, Austria.
  • Gastine S; Infection, Immunity and Inflammation Research and Teaching Department, University College London (UCL) Great Ormond Street Institute of Child Health, London, United Kingdom.
  • Standing JF; Infection, Immunity and Inflammation Research and Teaching Department, University College London (UCL) Great Ormond Street Institute of Child Health, London, United Kingdom.
  • Reljic R; Molecular Immunology Unit, Institute for Infection and Immunity, St. George's University of London, London, United Kingdom.
  • Teh AY; Molecular Immunology Unit, Institute for Infection and Immunity, St. George's University of London, London, United Kingdom.
  • Ma JK; Molecular Immunology Unit, Institute for Infection and Immunity, St. George's University of London, London, United Kingdom.
Front Plant Sci ; 14: 1126470, 2023.
Article en En | MEDLINE | ID: mdl-36923134
Introduction: Broadly neutralising antibodies are promising candidates for preventing and treating Human Immunodeficiency Virus/Acquired Immunodeficiency Syndrome (HIV/AIDS), as an alternative to or in combination with antiretroviral therapy (ART). These mAbs bind to sites on the virus essential for virus attachment and entry, thereby inhibiting entry into the host cell. However, the cost and availability of monoclonal antibodies, especially combinations of antibodies, hampers implementation of anti-HIV bNAb therapies in low- to middle- income countries (LMICs) where HIV-1 prevalence is highest. Methods: We have produced three HIV broadly neutralizing antibodies (bNAbs), 10-1074, VRC01 and 3BNC117 in the Nicotiana benthamiana transient expression system. The impact of specific modifications to enhance potency and efficacy were assessed. To prolong half-life and increase bioavailability, a M252Y/S254T/T256E (YTE) or M428L/N434S (LS) mutation was introduced. To increase antibody dependent cellular cytotoxicity (ADCC), we expressed an afucosylated version of each antibody using a glycoengineered plant line. Results: The majority of bNAbs and their variants could be expressed at yields of up to 47 mg/kg. Neither the expression system nor the modifications impacted the neutralization potential of the bNAbs. Afucosylated bNAbs exhibit enhanced ability to bind to FcγRIIIa and trigger ADCC, regardless of the presence of Fc amino acid mutations. Lastly, we demonstrated that Fc-modified variants expressed in plants show enhanced binding to FcRn, which results in a favourable in vivo pharmacokinetic profile compared to their unmodified counterparts. Conclusion: Tobacco plants are suitable expression hosts for anti-HIV bNAbs with increased efficacy and an improved pharmacokinetic profile.
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Texto completo: 1 Colección: 01-internacional Base de datos: MEDLINE Tipo de estudio: Risk_factors_studies Idioma: En Revista: Front Plant Sci Año: 2023 Tipo del documento: Article País de afiliación: Reino Unido Pais de publicación: Suiza

Texto completo: 1 Colección: 01-internacional Base de datos: MEDLINE Tipo de estudio: Risk_factors_studies Idioma: En Revista: Front Plant Sci Año: 2023 Tipo del documento: Article País de afiliación: Reino Unido Pais de publicación: Suiza