Designed proteins assemble antibodies into modular nanocages.

Area of Science:

• Biotechnology
• Structural Biology
• Immunology

Background:

• Multivalent antibody formats are sought after to improve binding avidity and signaling pathway agonism in biological and medical applications.
• Current methods lack general approaches for creating precisely oriented antibody assemblies with controlled valency.

Approach:

• Computational design of two-component nanocages using an antibody or Fc fusion and a designed Fc-binding homo-oligomer.
• Electron microscopy confirmed the structures of eight antibody nanocages across various architectures (dihedral, tetrahedral, octahedral, icosahedral) with controlled valency (2, 6, 12, 30 antibodies).

Key Points:

• Antibody nanocages targeting cell-surface receptors demonstrated enhanced signaling in DR5-mediated apoptosis, Tie2-mediated angiogenesis, CD40 activation, and T cell proliferation.
• Nanocage assembly significantly increased SARS-CoV-2 pseudovirus neutralization by specific monoclonal antibodies and Fc-ACE2 fusion proteins.

Conclusions:

• The developed method allows for the assembly of arbitrary antibodies into highly ordered structures with diverse geometries and valencies without covalent modification.
• This versatile approach is anticipated to have a broad impact on future developments in biology and medicine, particularly in therapeutic antibody engineering.