期刊
SCIENCE
卷 372, 期 6537, 页码 47-+出版社
AMER ASSOC ADVANCEMENT SCIENCE
DOI: 10.1126/science.abd9994
关键词
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资金
- NSF [CHE 1629214]
- HHMI
- Audacious Project at the Institute for Protein Design
- Washington Research Foundation
- NordstromBarrier Directors Fund at the Institute for Protein Design
- Washington State General Operating Fund for the Institute for Protein Design
- Wu Tsai Translational Investigator Fund
- Nan Fung Life Sciences Translational Investigator Fund
- NIH/NIDCR [T90 DE021984]
- NIH/NCATS [TR002318]
- NIH [R01AI127726]
- NIH/NCI Cancer Center Support Grant [P30 CA015704]
- ISCRM Pilot Award
- NIAID/NIH [DP1AI158186, HHSN272201700059C]
- NIGMS/NIH [R01GM120553]
- Pew Biomedical Scholars Award
- Burroughs Wellcome Investigators in the Pathogenesis of Infectious Diseases award
- University of Washington Arnold and Mabel Beckman cryoEM center
The computational design of antibody nanocages enhances the activity of antibodies targeting cell surface receptors and improves virus neutralization ability. These nanocages can effectively boost signaling pathways and play essential roles in various physiological processes.
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 alpha-SARS-CoV-2 monoclonal antibodies and Fc-angiotensin-converting enzyme 2 (ACE2) fusion proteins.
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