Fab-dimerized glycan-reactive antibodies are a structural category of natural antibodies

Wilton B Williams; R Ryan Meyerhoff; R J Edwards; Hui Li; Kartik Manne; Nathan I Nicely; Rory Henderson; Ye Zhou; Katarzyna Janowska; Katayoun Mansouri; Sophie Gobeil; Tyler Evangelous; Bhavna Hora; Madison Berry; A Yousef Abuahmad; Jordan Sprenz; Margaret Deyton; Victoria Stalls; Megan Kopp; Allen L Hsu; Mario J Borgnia; Guillaume B E Stewart-Jones; Matthew S Lee; Naomi Bronkema; M Anthony Moody; Kevin Wiehe; Todd Bradley; S Munir Alam; Robert J Parks; Andrew Foulger; Thomas Oguin; Gregory D Sempowski; Mattia Bonsignori; Celia C LaBranche; David C Montefiori; Michael Seaman; Sampa Santra; John Perfect; Joseph R Francica; Geoffrey M Lynn; Baptiste Aussedat; William E Walkowicz; Richard Laga; Garnett Kelsoe; Kevin O Saunders; Daniela Fera; Peter D Kwong; Robert A Seder; Alberto Bartesaghi; George M Shaw; Priyamvada Acharya; Barton F Haynes

doi:10.1016/j.cell.2021.04.042

Fab-dimerized glycan-reactive antibodies are a structural category of natural antibodies

Cell. 2021 May 27;184(11):2955-2972.e25. doi: 10.1016/j.cell.2021.04.042. Epub 2021 May 20.

Authors

Wilton B Williams¹, R Ryan Meyerhoff², R J Edwards², Hui Li³, Kartik Manne⁴, Nathan I Nicely⁴, Rory Henderson², Ye Zhou⁵, Katarzyna Janowska⁴, Katayoun Mansouri⁴, Sophie Gobeil⁴, Tyler Evangelous⁴, Bhavna Hora⁴, Madison Berry⁴, A Yousef Abuahmad⁴, Jordan Sprenz⁴, Margaret Deyton⁴, Victoria Stalls⁴, Megan Kopp⁴, Allen L Hsu⁶, Mario J Borgnia⁶, Guillaume B E Stewart-Jones⁷, Matthew S Lee⁸, Naomi Bronkema⁹, M Anthony Moody¹⁰, Kevin Wiehe², Todd Bradley⁴, S Munir Alam², Robert J Parks⁴, Andrew Foulger⁴, Thomas Oguin⁴, Gregory D Sempowski², Mattia Bonsignori², Celia C LaBranche¹¹, David C Montefiori¹², Michael Seaman¹³, Sampa Santra¹³, John Perfect¹⁴, Joseph R Francica⁷, Geoffrey M Lynn¹⁵, Baptiste Aussedat¹⁶, William E Walkowicz¹⁶, Richard Laga¹⁷, Garnett Kelsoe¹⁸, Kevin O Saunders¹⁹, Daniela Fera⁹, Peter D Kwong⁷, Robert A Seder⁷, Alberto Bartesaghi²⁰, George M Shaw³, Priyamvada Acharya²¹, Barton F Haynes²²

Affiliations

¹ Duke Human Vaccine Institute, Durham, NC 27710, USA; Department of Medicine, Duke University, Durham, NC 27710, USA. Electronic address: wilton.williams@duke.edu.
² Duke Human Vaccine Institute, Durham, NC 27710, USA; Department of Medicine, Duke University, Durham, NC 27710, USA.
³ Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA 19104, USA.
⁴ Duke Human Vaccine Institute, Durham, NC 27710, USA.
⁵ Department of Computer Science, Duke University, Durham, NC 27708, USA.
⁶ Genome Integrity and Structural Biology Laboratory, NIEHS, NIH, Department of Health and Human Services, Research Triangle Park, NC 27709, USA.
⁷ Vaccine Research Center, NIAID, NIH, Bethesda, MD 20892, USA.
⁸ Boston Children's Hospital and Harvard Medical School, Boston, MA 02115, USA.
⁹ Department of Chemistry and Biochemistry, Swarthmore College, Swarthmore, PA 19081, USA.
¹⁰ Duke Human Vaccine Institute, Durham, NC 27710, USA; Department of Immunology, Duke University, Durham, NC 27710, USA; Department of Pediatrics, Duke University, Durham, NC 27710, USA.
¹¹ Department of Surgery, Duke University, Durham, NC 27710, USA.
¹² Duke Human Vaccine Institute, Durham, NC 27710, USA; Department of Surgery, Duke University, Durham, NC 27710, USA.
¹³ Beth Israel Deaconess Medical Center and Harvard Medical School, Boston, MA 02215, USA.
¹⁴ Department of Medicine, Duke University, Durham, NC 27710, USA.
¹⁵ Vaccine Research Center, NIAID, NIH, Bethesda, MD 20892, USA; Avidea Technologies, Inc., Baltimore, MD, USA.
¹⁶ Memorial Sloan Kettering Cancer Center, New York, NY 10065, USA.
¹⁷ Institute of Macromolecular Chemistry, Czech Academy of Sciences, Prague, Czech Republic.
¹⁸ Duke Human Vaccine Institute, Durham, NC 27710, USA; Department of Immunology, Duke University, Durham, NC 27710, USA.
¹⁹ Duke Human Vaccine Institute, Durham, NC 27710, USA; Department of Immunology, Duke University, Durham, NC 27710, USA; Department of Surgery, Duke University, Durham, NC 27710, USA.
²⁰ Department of Computer Science, Duke University, Durham, NC 27708, USA; Department of Biochemistry, Duke University, Durham, NC 27705, USA; Department of Electrical and Computer Engineering, Duke University, Durham, NC 27708, USA.
²¹ Duke Human Vaccine Institute, Durham, NC 27710, USA; Department of Surgery, Duke University, Durham, NC 27710, USA. Electronic address: priyamvada.acharya@duke.edu.
²² Duke Human Vaccine Institute, Durham, NC 27710, USA; Department of Medicine, Duke University, Durham, NC 27710, USA; Department of Immunology, Duke University, Durham, NC 27710, USA. Electronic address: hayne002@mc.duke.edu.

Abstract

Natural antibodies (Abs) can target host glycans on the surface of pathogens. We studied the evolution of glycan-reactive B cells of rhesus macaques and humans using glycosylated HIV-1 envelope (Env) as a model antigen. 2G12 is a broadly neutralizing Ab (bnAb) that targets a conserved glycan patch on Env of geographically diverse HIV-1 strains using a unique heavy-chain (V_H) domain-swapped architecture that results in fragment antigen-binding (Fab) dimerization. Here, we describe HIV-1 Env Fab-dimerized glycan (FDG)-reactive bnAbs without V_H-swapped domains from simian-human immunodeficiency virus (SHIV)-infected macaques. FDG Abs also recognized cell-surface glycans on diverse pathogens, including yeast and severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) spike. FDG precursors were expanded by glycan-bearing immunogens in macaques and were abundant in HIV-1-naive humans. Moreover, FDG precursors were predominately mutated IgM⁺IgD⁺CD27⁺, thus suggesting that they originated from a pool of antigen-experienced IgM⁺ or marginal zone B cells.

Keywords: FDG Abs; Fab dimerization; HIV-1 Env glycans; IgM-memory B cells; SARS-CoV-2 spike glycans; glycan-dependent Ab binding; marginal zone B cells; natural Abs.

Publication types

Research Support, N.I.H., Extramural
Research Support, Non-U.S. Gov't

MeSH terms

Animals
Antibodies, Neutralizing / immunology*
B-Lymphocytes / immunology
Broadly Neutralizing Antibodies / immunology
COVID-19 / immunology
Dimerization
Epitopes / immunology
Glycosylation
HIV Antibodies / immunology
HIV Infections / immunology
HIV-1 / immunology*
Humans
Immunoglobulin Fab Fragments / chemistry
Immunoglobulin Fab Fragments / immunology*
Macaca mulatta
Polysaccharides / chemistry
Polysaccharides / immunology*
Receptors, Antigen, B-Cell / chemistry
SARS-CoV-2 / immunology*
Simian Immunodeficiency Virus / genetics
Simian Immunodeficiency Virus / immunology*
Spike Glycoprotein, Coronavirus / immunology*
Vaccines / immunology
env Gene Products, Human Immunodeficiency Virus / chemistry
env Gene Products, Human Immunodeficiency Virus / genetics
env Gene Products, Human Immunodeficiency Virus / immunology*

Substances

Antibodies, Neutralizing
Broadly Neutralizing Antibodies
Epitopes
HIV Antibodies
Immunoglobulin Fab Fragments
Polysaccharides
Receptors, Antigen, B-Cell
Spike Glycoprotein, Coronavirus
Vaccines
env Gene Products, Human Immunodeficiency Virus
spike protein, SARS-CoV-2

Abstract

Publication types

MeSH terms

Substances

Grants and funding