Designed proteins assemble antibodies into modular nanocages.
Robby Divine1,2, Ha V Dang1, George Ueda1,2
1Department of Biochemistry, University of Washington, Seattle, WA 98195, USA.
Science (New York, N.Y.)
|April 2, 2021
Summary
Computational design of antibody nanocages enhances therapeutic antibody activity. These novel structures improve signaling for cell surface receptors and increase neutralization of SARS-CoV-2 pseudoviruses.
Area of Science:
- Biotechnology
- Structural Biology
- Immunology
Background:
- Multivalent display of antibodies or ligands can significantly enhance their biological activity.
- Traditional methods involve attaching antibodies to pre-existing scaffolds, which can be inefficient.
Purpose of the Study:
- To computationally design novel antibody nanocages that integrate antibody function with structural assembly.
- To create multivalent antibody displays using self-assembling protein nanocages.
Main Methods:
- Computational design of antibody-binding homo-oligomers and antibody-based structural components.
- Nanocage assembly driven by the interaction between designed protein components.
- Electron microscopy to determine the structures of assembled nanocages.
- Functional assays to evaluate enhanced signaling and neutralization activities.
Main Results:
- Successfully designed and assembled eight distinct nanocage architectures (dihedral, tetrahedral, octahedral, icosahedral) displaying 2, 6, 12, and 30 antibodies per nanocage.
- Electron microscopy structures closely matched computational models.
- Demonstrated enhanced receptor-mediated signaling for death receptor 5 (DR5), angiopoietin-1 receptor (Tie2), CD40 activation, and T cell proliferation compared to free antibodies.
- Showed increased neutralization of SARS-CoV-2 pseudoviruses by antibody nanocages.
Conclusions:
- Computationally designed antibody nanocages offer a powerful platform for creating multivalent antibody displays.
- This approach enhances antibody efficacy in various biological contexts, including immune activation and viral neutralization.
- The self-assembly mechanism provides a versatile strategy for engineering novel protein-based therapeutics.
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