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).
