The crystal structure of a domain of TRIM21 (blue) interacting with the Fc region of an antibody (grey). The engineered sites of the Fc region are shown in red.

© 2019 A*STAR Singapore Immunology Network

Targeting TRIM21 for stronger, safer vaccines

16 Oct 2019

A*STAR scientists have found a way to strengthen the immune response to adenovirus infection using engineered antibodies.

When a virus enters a cell, it hijacks the cell’s functions and turns it into a factory that produces more viruses. Dendritic cells (DCs)—a type of white blood cell in the body—play a crucial role in activating other cells in the immune system to contain the infection.

To accomplish their mission, DCs engulf immune complexes which are made up of antibodies bound to an invading virus. The immune complexes are then ‘cut up’ and displayed on the surface of DCs in a process known as antigen cross-presentation.

Subsequently, another subset of immune cells called T cells encounter these antigen-presenting DCs and become activated, maturing into killer T cells that hunt down virus-infected cells. Enhancing DC function could therefore lead to better clearance of infections.

In this study, researchers from A*STAR’s Institute of Molecular and Cell Biology (IMCB) and Singapore Immunology Network (SIgN), led by Cheng-I Wang, focused on how a protein called TRIM21 mediates the immune response to adenoviruses, a class of viruses that can cause conjunctivitis or gastroenteritis, among other health conditions. They focused on TRIM21 because the protein is involved in the degradation of the immune complexes and mediates signaling inside DCs.

“TRIM21 binds to a segment known as the Fc region of the antibody in immune complexes. We hypothesized that a more stable TRIM21-Fc complex in DCs may result in stronger immune responses,” said Wang.

Although the structure of the TRIM21-Fc complex is known, mutations in the Fc region that would enhance TRIM21-binding could not be predicted. Hence, Wang’s team generated two billion antibody variants with mutations in the Fc/TRIM21 interface. This allowed them to isolate an antibody that has 100 times higher affinity to TRIM21 than typical antibodies.

The researchers demonstrated that their high-affinity antibody enhanced DC activation and maturation, which in turn resulted in a significant expansion of killer T cell populations targeting adenovirus-infected cells. They noted that stronger TRIM21 binding antibodies may have profound implications for the development of safer and more effective vaccines that rely on weakened live viruses to generate an immune response from the body.

“Our vaccine, like recombinant or subunit vaccines, will be safer. At the same time, it can induce strong immune responses through enhanced Fc-TRIM21 interaction,” said Wang.

“Going forward, we want to verify if our findings in vitro remain true in vivo. Using mouse models of human disease, we will be testing viral and cancer vaccines that carry antigens to DCs via Fc-engineered antibodies,” he said.

The A*STAR-affiliated researchers contributing to this research are from the Institute of Molecular and Cell Biology (IMCB) and the Singapore Immunology Network (SIgN).

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Ng, P. M. L, Kaliaperumal, N., Lee, C. Y., Chin, W. J., Tan, H. C. et al. Enhancing Antigen Cross-Presentation in Human Monocyte-Derived Dendritic Cells by Recruiting the Intracellular Fc Receptor TRIM21. Journal of Immunology 202, 2307-2319 (2019) | article

About the Researcher

Cheng-I Wang

Principal Investigator

Singapore Immunology Network
Cheng-I Wang received a PhD degree in chemistry from Washington University and completed his postdoctoral training in the department of pharmaceutical chemistry at the University of California, San Francisco. Wang worked on drug discovery projects at biotechnology and pharmaceutical companies in the US before joining the A*STAR Singapore Immunology Network (SIgN) in 2009. As Head of the Human Monoclonal Antibody Technology Platform at SIgN, Wang works on the discovery and development of human antibodies against infection and immune disorders, using combinatorial approaches to incorporate novel functions into protein and antibody molecules.

This article was made for A*STAR Research by Wildtype Media Group