1. Designed proteins assemble antibodies into modular nanocages.
- Author
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Divine R, Dang HV, Ueda G, Fallas JA, Vulovic I, Sheffler W, Saini S, Zhao YT, Raj IX, Morawski PA, Jennewein MF, Homad LJ, Wan YH, Tooley MR, Seeger F, Etemadi A, Fahning ML, Lazarovits J, Roederer A, Walls AC, Stewart L, Mazloomi M, King NP, Campbell DJ, McGuire AT, Stamatatos L, Ruohola-Baker H, Mathieu J, Veesler D, and Baker D
- Subjects
- Angiopoietins chemistry, Angiopoietins immunology, Angiopoietins metabolism, Antibodies, Monoclonal chemistry, Antibodies, Monoclonal immunology, Antibodies, Neutralizing chemistry, Antibodies, Neutralizing immunology, Antibodies, Viral chemistry, Antibodies, Viral immunology, B-Lymphocytes immunology, CD40 Antigens chemistry, CD40 Antigens immunology, CD40 Antigens metabolism, Cell Line, Tumor, Cell Proliferation, Computer Simulation, Genes, Synthetic, Humans, Immunoglobulin Fc Fragments chemistry, Lymphocyte Activation, Models, Molecular, Protein Binding, Receptor, TIE-2 metabolism, Receptors, TNF-Related Apoptosis-Inducing Ligand immunology, Receptors, TNF-Related Apoptosis-Inducing Ligand metabolism, SARS-CoV-2 immunology, T-Lymphocytes immunology, T-Lymphocytes physiology, Antibodies chemistry, Antibodies immunology, Nanostructures, Protein Engineering, Signal Transduction
- Abstract
Multivalent display of receptor-engaging antibodies or ligands can enhance their activity. Instead of achieving multivalency by attachment to preexisting scaffolds, here we unite form and function by the computational design of nanocages in which one structural component is an antibody or Fc-ligand fusion and the second is a designed antibody-binding homo-oligomer that drives nanocage assembly. Structures of eight nanocages determined by electron microscopy spanning dihedral, tetrahedral, octahedral, and icosahedral architectures with 2, 6, 12, and 30 antibodies per nanocage, respectively, closely match the corresponding computational models. Antibody nanocages targeting cell surface receptors enhance signaling compared with free antibodies or Fc-fusions in death receptor 5 (DR5)-mediated apoptosis, angiopoietin-1 receptor (Tie2)-mediated angiogenesis, CD40 activation, and T cell proliferation. Nanocage assembly also increases severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) pseudovirus neutralization by α-SARS-CoV-2 monoclonal antibodies and Fc-angiotensin-converting enzyme 2 (ACE2) fusion proteins., (Copyright © 2021 The Authors, some rights reserved; exclusive licensee American Association for the Advancement of Science. No claim to original U.S. Government Works.)
- Published
- 2021
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