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Structural and functional characterization of capsid binding by anti-AAV9 monoclonal antibodies from infants after SMA gene therapy.
Logan, Grant J; Mietzsch, Mario; Khandekar, Neeta; D'Silva, Arlene; Anderson, Daniel; Mandwie, Mawj; Hsi, Jane; Nelson, Austin R; Chipman, Paul; Jackson, Jennifer; Schofield, Peter; Christ, Daniel; Goodnow, Christopher C; Reed, Joanne H; Farrar, Michelle A; McKenna, Robert; Alexander, Ian E.
Affiliation
  • Logan GJ; Gene Therapy Research Unit, Children's Medical Research Institute, Faculty of Medicine and Health, The University of Sydney and Sydney Children's Hospitals Network, Westmead, NSW, Australia.
  • Mietzsch M; Department of Biochemistry and Molecular Biology, Center for Structural Biology, McKnight Brain Institute, College of Medicine, University of Florida, Gainesville, FL, USA.
  • Khandekar N; Gene Therapy Research Unit, Children's Medical Research Institute, Faculty of Medicine and Health, The University of Sydney and Sydney Children's Hospitals Network, Westmead, NSW, Australia.
  • D'Silva A; School of Women's and Children's Health, University of New South Wales Medicine, UNSW Sydney, Sydney, NSW, Australia.
  • Anderson D; Gene Therapy Research Unit, Children's Medical Research Institute, Faculty of Medicine and Health, The University of Sydney and Sydney Children's Hospitals Network, Westmead, NSW, Australia.
  • Mandwie M; Gene Therapy Research Unit, Children's Medical Research Institute, Faculty of Medicine and Health, The University of Sydney and Sydney Children's Hospitals Network, Westmead, NSW, Australia.
  • Hsi J; Department of Biochemistry and Molecular Biology, Center for Structural Biology, McKnight Brain Institute, College of Medicine, University of Florida, Gainesville, FL, USA.
  • Nelson AR; Department of Biochemistry and Molecular Biology, Center for Structural Biology, McKnight Brain Institute, College of Medicine, University of Florida, Gainesville, FL, USA.
  • Chipman P; Department of Biochemistry and Molecular Biology, Center for Structural Biology, McKnight Brain Institute, College of Medicine, University of Florida, Gainesville, FL, USA.
  • Jackson J; Garvan Institute of Medical Research, UNSW Sydney, Faculty of Medicine, Darlinghurst, NSW, Australia.
  • Schofield P; Garvan Institute of Medical Research, UNSW Sydney, Faculty of Medicine, Darlinghurst, NSW, Australia.
  • Christ D; Garvan Institute of Medical Research, UNSW Sydney, Faculty of Medicine, Darlinghurst, NSW, Australia.
  • Goodnow CC; Garvan Institute of Medical Research, UNSW Sydney, Faculty of Medicine, Darlinghurst, NSW, Australia; St. Vincent's Clinical School, Faculty of Medicine, UNSW Sydney, Darlinghurst, NSW, Australia.
  • Reed JH; Westmead Institute for Medical Research, Centre for Immunology and Allergy Research, Westmead, NSW, Australia.
  • Farrar MA; School of Women's and Children's Health, University of New South Wales Medicine, UNSW Sydney, Sydney, NSW, Australia; Department of Neurology, Sydney Children's Hospital, Randwick, NSW, Australia.
  • McKenna R; Department of Biochemistry and Molecular Biology, Center for Structural Biology, McKnight Brain Institute, College of Medicine, University of Florida, Gainesville, FL, USA.
  • Alexander IE; Gene Therapy Research Unit, Children's Medical Research Institute, Faculty of Medicine and Health, The University of Sydney and Sydney Children's Hospitals Network, Westmead, NSW, Australia; Discipline of Child and Adolescent Health, University of Sydney, Westmead, NSW, Australia. Electronic address
Mol Ther ; 31(7): 1979-1993, 2023 07 05.
Article in En | MEDLINE | ID: mdl-37012705
ABSTRACT
Success in the treatment of infants with spinal muscular atrophy (SMA) underscores the potential of vectors based on adeno-associated virus (AAV). However, a major obstacle to the full realization of this potential is pre-existing natural and therapy-induced anti-capsid humoral immunity. Structure-guided capsid engineering is one possible approach to surmounting this challenge but necessitates an understanding of capsid-antibody interactions at high molecular resolution. Currently, only mouse-derived monoclonal antibodies (mAbs) are available to structurally map these interactions, which presupposes that mouse and human-derived antibodies are functionally equivalent. In this study, we have characterized the polyclonal antibody responses of infants following AAV9-mediated gene therapy for SMA and recovered 35 anti-capsid mAbs from the abundance of switched-memory B (smB) cells present in these infants. For 21 of these mAbs, seven from each of three infants, we have undertaken functional and structural analysis measuring neutralization, affinities, and binding patterns by cryoelectron microscopy (cryo-EM). Four distinct patterns were observed akin to those reported for mouse-derived mAbs, but with early evidence of differing binding pattern preference and underlying molecular interactions. This is the first human and largest series of anti-capsid mAbs to have been comprehensively characterized and will prove to be powerful tools for basic discovery and applied purposes.
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Full text: 1 Collection: 01-internacional Database: MEDLINE Main subject: Capsid / Antibodies, Monoclonal Limits: Animals / Humans / Infant Language: En Journal: Mol Ther Journal subject: BIOLOGIA MOLECULAR / TERAPEUTICA Year: 2023 Type: Article Affiliation country: Australia
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Full text: 1 Collection: 01-internacional Database: MEDLINE Main subject: Capsid / Antibodies, Monoclonal Limits: Animals / Humans / Infant Language: En Journal: Mol Ther Journal subject: BIOLOGIA MOLECULAR / TERAPEUTICA Year: 2023 Type: Article Affiliation country: Australia