Designed proteins assemble antibodies into modular nanocages

With cues from nature, designing functional molecules enables scientists to nanoengineer and customize for specific uses. For example, designing antibodies that are widely used as therapeutic and diagnostic protein tools may revolutionize the healthcare landscape.  

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It is well known that multivalent antibodies increase binding avidity. It also enhances signaling pathway agonism through receptor clustering. However, to form a precise and oriented antibody assembly with a controlled valency is a challenge.

In a recent bioRxiv* preprint publication, Professor David Baker and his interdisciplinary team of researchers present the computational design of two-component nanocages - that drive the assembly of antibodies. They develop technology to allow the design of the protein using form and function to enable the researchers to control.

Researchers have fashioned antibody-binding, cage-forming oligomers through rigid helical fusion that provides a wide range of geometries and orientations.

The current techniques that are available for creating multivalent-antibodies include chaining together 1) multiple antigen-binding fragments, 2) pentameric immunoglobulin M (IgM) or IgM derivatives such as fragment crystallizable (Fc) domain hexamers, 3) inorganic materials fused to multiple dimeric immunoglobulin G (IgG) antibodies, or 4) protein oligomers or nanoparticles to which immunoglobulin (Ig) or Ig-binding domains are linked.

However, these approaches require extensive engineering or multi-step conjugation reactions to achieve the desired antibody oligomer. Even in the case of nanoparticles with flexibly linked Ig-binding domains, it is difficult to ensure full IgG occupancy on the particle surface. When multiple nanoparticles bind to dimeric IgGs, particle flocculation is induced.

In this study, a general computational method for antibody cage design uses the symmetry of the protein building blocks to align with a larger target architecture. First, they design an antibody-binding, nanocage-forming protein that precisely arranges IgG dimers along the two-fold symmetry axes of a target architecture.

Symmetric protein assemblies could also be built out of IgG antibodies, which are two-fold symmetric proteins, by placing the symmetry axes of the antibodies on the two-fold axes of the target architecture and designing a second protein to hold the antibodies in the correct orientation.”

They fuse three types of “building block” proteins: antibody Fc-binding proteins, monomeric helical linkers, and cyclic oligomers. Each of these has a functional role in the final nanocage structure. The designed cage-forming protein is thus a cyclic oligomer; it terminates in antibody-binding domains that bind IgG antibodies at the orientations required for the proper formation of antibody nanocages (hereafter AbCs, for Antibody Cages).

The researchers then expressed the designed protein sequences in E. coli using synthetic genes. The proteins were purified using chromatographic techniques. The structural characterization is studied using small-angle X-ray scattering (SAXS) and electron microscopy (EM), and stability is determined by Dynamic light scattering (DLS).

These studies demonstrate that the nanocages exhibit monodispersity comparable to IgM and control over binding domain valency and positioning.

They assembled antibodies and Fc fusions into different nanocages geometry targeting a variety of signaling pathways. Using the designed AbCs as a general platform, the team systematically investigated the effect of valency and geometry of receptor engagement on the signaling pathway activation (RTK- and TNFR-family cell-surface receptors).

This approach has the advantage of much higher structural homogeneity, allowing more precise tuning of phenotypic effects and more controlled formulation, the researchers write.

It is important to note that the researchers also assembled ⍺-SARS-CoV-2 (severe acute respiratory syndrome coronavirus 2) antibodies into nanocages to increase SARS-CoV-2 neutralization using apoferritin to scaffold binding domains. They found that the octahedral AbCs of Fc-ACE2 (which directly engages the receptor-binding domain of the spike protein) enhanced neutralization around 7-fold compared to free Fc-ACE2 fusion for SARS-CoV-2 pseudovirus and 2.5- fold for SARS-CoV-1 pseudovirus.

In the wake of the COVID-19 pandemic, the development of antibodies targeting the SARS-CoV-2 spike (S) protein for prophylaxis and post-exposure therapy is researched extensively. The positive results observed in this study are highly encouraging for future antiviral strategies.

In this study, the researchers claim that they are proposing a method for the first time that can create antibody-based protein nanoparticles across multiple valencies with precisely-controlled geometry and composition (that apply to the vast number of off-the-shelf IgG antibodies). With this strong possibility of controlled high-valent antibody-design, it is just a matter of time before effectively overcoming diverse antigens from nature.

We could wait another million years for the protein we need to evolve, or we could design it ourselves,”


*Important Notice

bioRxiv publishes preliminary scientific reports that are not peer-reviewed and, therefore, should not be regarded as conclusive, guide clinical practice/health-related behavior, or treated as established information.

Journal references:
  • Designed proteins assemble antibodies into modular nanocages
  • Robby Divine, Ha V. Dang, George Ueda, Jorge A. Fallas, Ivan Vulovic, William Sheffler, Shally Saini, Yan Ting Zhao, Infencia Xavier Raj, Peter A. Morawski, Madeleine F. Jennewein, Leah J. Homad, Yu-Hsin Wan, Marti R. Tooley, Franziska Seeger, Mitchell L. Fahning, Ali Etemadi, James Lazarovits, Alex Roederer, Alexandra C. Walls, Lance Stewart, Mohammadali Mazloomi, Neil P. King, Daniel J. Campbell, Andrew T. McGuire, Leonidas Stamatatos, Hannele Ruohola-Baker, Julie Mathieu, David Veesler, David Baker bioRxiv 2020.12.01.406611; doi:

Dr. Ramya Dwivedi

Written by

Dr. Ramya Dwivedi

Ramya has a Ph.D. in Biotechnology from the National Chemical Laboratories (CSIR-NCL), in Pune. Her work consisted of functionalizing nanoparticles with different molecules of biological interest, studying the reaction system and establishing useful applications.


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