Highlights

In brief

A systematic comparison of eight distinct formats of T-cell-engaging bispecific antibodies reveals critical insights into the molecular designs for optimal biological activity and manufacturability.

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Blueprints to optimise a cancer killer

20 Dec 2023

A*STAR researchers tackle the challenge of creating therapeutic antibodies that effectively kill tumours and are also easily scalable in manufacturing settings.

Think of tumours as masters of disguise. By masquerading as healthy tissues and creating a molecular shield of invisibility, cancer cells evade the immune system’s surveillance. However, a next-generation therapeutic modality aims to unmask tumours, exposing them for immune destruction.

T-cell-engaging bispecific antibodies (T-bsAbs) have binding ‘arms’ which guide T cells to tumours hiding in stealth mode. They have a molecular design space that reflects the complexity of treating diverse tumour types—their shape, size and binding properties can all be tailored to maximise their potency as antibody therapies.

“Understanding the interplay of these factors is crucial for achieving the desired therapeutic effect from a T-bsAb,” said Yuan Sheng Yang, Group Leader at A*STAR’s Bioprocessing Technology Institute (BTI).

However, the drug development industry has found it challenging to fine-tune T-bsAbs, as modifying antibody structures to boost their functions often also makes them more costly to manufacture.

In close collaboration with Group Leader Shengli Xu and colleagues from A*STAR's Singapore Immunology Network (SIgN), Yang’s team systematically compared eight commonly-used T-bsAb designs to connect the dots between molecular design, ease of manufacture and therapeutic efficacy.

To test how different antibody components—such as antigen-binding fragments (Fabs) and single-chain variable fragments (scFvs)—can affect the overall molecule, the researchers designed T-bsAbs with unique combinations thereof. They then generated specialised cell lines to mass produce their T-bsAb designs before assessing them on yield, purity, binding properties and biological activity.

“Achieving a stable bsAb product is key to reducing production costs, as it would enhance overall product yield and quality,” said Yang.

The study demonstrated that some antibody designs, such as those with more scFv components, were highly prone to aggregation: a production flaw where antibody molecules tangle up in clusters and ruin their ability to bind targets. Too much aggregation can lead to reduced overall production yields and drive costs up, Yang added.

At the same time, therapeutic efficacy remains the paramount concern for any T-bsAb drug candidate. “We observed that some T-bsAbs behaved very differently when activating T cells and eradicating tumour cells, even when they seemed similarly highly stable and manufacturable,” said Xu.

Based on their results, the researchers homed in on two T-bsAb formats—each bearing one scFv component—that struck the balance between manufacturability and tumour cell-killing potency. According to Xu, these critical insights can streamline the development of improved, easy-to-manufacture cancer immunotherapies.

Looking ahead, Yang said that emerging technologies such as artificial intelligence and computational modelling can accelerate the rational design of T-bsAbs with enhanced therapeutic properties. “The field's potential to provide more effective and accessible treatments across a spectrum of medical conditions holds great promise for the coming years,” Yang added.

The A*STAR-affiliated researchers contributing to this research are from the Bioprocessing Technology Institute (BTI) and Singapore Immunology Network (SIgN).

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References

Loh, H.P., Mahfut, F.B., Chen, S.W., Huang, Y., Huo, J., et al. Manufacturability and functionality assessment of different formats of T-cell engaging bispecific antibodies. mAbs 15 (1), 2231129 (2023). | article

About the Researchers

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Yuan Sheng Yang

Scientist and Group Leader

Bioprocessing Technology Institute (BTI)
Yuan Sheng Yang received his doctorate degree from the Department of Chemical Engineering at Vanderbilt University in 2005. Upon graduation, he joined A*STAR's Bioprocessing Technology Institute (BTI), where he currently heads the Cell Line Development group that develops platform technologies for accelerating cell-line and antibody development. He has published 64 peer reviewed papers, has filed nine patents, and his cell-line and antibody development platform technologies have been licensed to dozens of companies. The CHO cell line platform Yang helped developed in collaboration with industry partners features unrivalled productivity and speed, enabling the development of five antibody drugs into clinical trials.
Shengli Xu joined the Institute of Molecular and Cell Biology (IMCB), Singapore, beginning his PhD studies in 1998. Upon obtaining his PhD in Immunology in 2003, Xu pursued postdoctoral research, first as a Research Fellow at IMCB, and later as a Senior Research Fellow at Singapore Immunology Network (SIgN) until 2009. In 2009, he joined Bioprocessing Technology Institute (BTI) as a Research Scientist and progressed to become a Senior Lead Research Scientist and a Group Leader. In 2020, Xu rejoined SIgN as a Principal investigator to lead the B Cell Immunology Group. He is also an adjunction assistant professor at the Department of Physiology, NUS. Xu’s research primarily focuses on B-cell immunology and the development of antibody-based immunotherapy.
Kong-Peng Lam obtained his PhD in Immunology in 1994 from the College of Physicians & Surgeons at Columbia University, US. He then carried out postdoctoral research at the Institute for Genetics, University of Cologne, working to understand B cell biology and development. He is currently the Executive Director of A*STAR’s Singapore Immunology Network (SIgN), a Professor in the Departments of Microbiology and Immunology, Physiology, and Pediatrics at Yong Loo Lin School of Medicine, National University of Singapore (NUS), and an Adjunct Professor in the School of Biological Sciences at Nanyang Technological University (NTU).

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