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Designed Proteins Assemble Antibodies Into Modular Nanocages Publisher Pubmed



Divine R1, 2 ; Dang HV1 ; Ueda G1, 2 ; Fallas JA1, 2 ; Vulovic I1, 2 ; Sheffler W2 ; Saini S1, 3 ; Zhao YT1, 3, 4 ; Raj IX1, 3 ; Morawski PA5 ; Jennewein MF6 ; Homad LJ6 ; Wan YH6 ; Tooley MR2 Show All Authors
Authors
  1. Divine R1, 2
  2. Dang HV1
  3. Ueda G1, 2
  4. Fallas JA1, 2
  5. Vulovic I1, 2
  6. Sheffler W2
  7. Saini S1, 3
  8. Zhao YT1, 3, 4
  9. Raj IX1, 3
  10. Morawski PA5
  11. Jennewein MF6
  12. Homad LJ6
  13. Wan YH6
  14. Tooley MR2
  15. Seeger F1, 2
  16. Etemadi A2, 7
  17. Fahning ML5
  18. Lazarovits J1, 2
  19. Roederer A2
  20. Walls AC1
  21. Stewart L2
  22. Mazloomi M7
  23. King NP1, 2
  24. Campbell DJ5
  25. Mcguire AT6, 8
  26. Stamatatos L6, 8
  27. Ruoholabaker H1, 3
  28. Mathieu J3, 9
  29. Veesler D1
  30. Baker D1, 2, 10

Source: Science Published:2021


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 a-SARS-CoV-2 monoclonal antibodies and Fc-angiotensinconverting enzyme 2 (ACE2) fusion proteins. © 2021 American Association for the Advancement of Science. All rights reserved.
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