ORCID Profile
0000-0002-8046-3667
Current Organisation
Garvan Institute of Medical Research
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Publisher: Cold Spring Harbor Laboratory
Date: 20-10-2022
DOI: 10.1101/2022.10.19.512954
Abstract: Emerging variants of concern (VOCs) are threatening to limit the effectiveness of SARS-CoV-2 monoclonal antibodies and vaccines currently used in clinical practice broadly neutralizing antibodies and strategies for their identification are therefore urgently required. Here we demonstrate that broadly neutralizing antibodies can be isolated from peripheral blood mononuclear cells (PBMCs) of convalescent patients using SARS-CoV-2 receptor binding domains (RBDs) carrying epitope-specific mutations. This is exemplified by two human antibodies, GAR05, binding to epitope class 1, and GAR12, binding to a new epitope class 6 (located between class 3 and class 5). Both antibodies broadly neutralize VOCs, exceeding the potency of the clinical monoclonal sotrovimab (mAb S309) by orders of magnitude. They also provide potent prophylactic and therapeutic in vivo protection of hACE2 mice against viral challenge. Our results indicate that exposure to Wuhan SARS-CoV-2 induces antibodies that maintain potent and broad neutralization against emerging VOCs using two unique strategies: either by targeting the ergent class 1 epitope in a manner resistant to VOCs (ACE2 mimicry, as illustrated by GAR05 and mAbs P2C-1F11/S2K14) or alternatively, by targeting rare and highly conserved epitopes, such as the new class 6 epitope identified here (as illustrated by GAR12). Our results provide guidance for next generation monoclonal antibody development and vaccine design.
Publisher: American Association for the Advancement of Science (AAAS)
Date: 17-09-2021
Abstract: Prolactin-humanized mice promote growth and metastatic progression of estrogen-dependent patient-derived breast cancer.
Publisher: American Association for the Advancement of Science (AAAS)
Date: 13-04-2018
Abstract: Antibodies distinguish foreign epitopes from closely related self-antigens by poorly understood mechanisms. In mice, Burnett et al. found that a proportion of B cells could cross-react with similar foreign and self-antigens (see the Perspective by Kara and Nussenzweig). Challenge with self-antigen resulted in anergy (i.e., a lack of immune response), which was reversed by exposure to high-density foreign antigen. Mutations that decreased self-affinity were rapidly selected for, whereas selection for epistatic mutations that enhanced foreign reactivity took longer. Self-reactivity, rather than being an impediment to immunization, resulted in higher affinities against a foreign immunogen. Science , this issue p. 223 see also p. 152
Publisher: Proceedings of the National Academy of Sciences
Date: 08-07-2022
Abstract: Humans lack the capacity to produce the Galα1–3Galβ1–4GlcNAc (α-gal) glycan, and produce anti-α-gal antibodies upon exposure to the carbohydrate on a erse set of immunogens, including commensal gut bacteria, malaria parasites, cetuximab, and tick proteins. Here we use X-ray crystallographic analysis of antibodies from α-gal knockout mice and humans in complex with the glycan to reveal a common binding motif, centered on a germline-encoded tryptophan residue at Kabat position 33 (W33) of the complementarity-determining region of the variable heavy chain (CDRH1). Immunoglobulin sequencing of anti-α-gal B cells in healthy humans and tick-induced mammalian meat anaphylaxis patients revealed preferential use of heavy chain germline IGHV3-7, encoding W33, among an otherwise highly polyclonal antibody response. Antigen binding was critically dependent on the presence of the germline-encoded W33 residue for all of the analyzed antibodies moreover, introduction of the W33 motif into naive IGHV3-23 antibody phage libraries enabled the rapid selection of α-gal binders. Our results outline structural and genetic factors that shape the human anti-α-galactosyl antibody response, and provide a framework for future therapeutics development.
No related grants have been discovered for Peter Schofield.