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Bispecific T-cell engagers (TcEs) are immunotherapeutic drugs that link cancer cells to T cells via specific surface molecules called antigens. They work by directing the T cells to attack and kill the cancer. There has been some variability in the potency and effectiveness of different TcE designs and the researchers at the Kennedy Institute, University of Oxford, in collaboration with Boehringer Ingelheim, designed a series of TcEs with different parameters to understand the factors that influence TcE potency.
Michael Dustin, Kennedy Trust Professor of Molecular Immunology said: ‘TcEs are innovative drugs designed to link T cells – our body’s natural defenders – to cancer cells, enabling a targeted attack on tumours. It’s been suggested that close membrane-to-membrane contact (≤13 nm) is a key mechanism of TcE function, but many approved TcE appear to too large. We aimed to explore this further and uncover additional mechanisms that could explain the high potency of larger TcE.’
In the new study published in the Proceedings of the National Academy of Sciences, the researchers designed a series of four distinct TcE formats that varied the spacing between the binding sites that recognise the cancer target (HER2) and the T cell receptor. Using small-angle X-ray scattering, they found that these TcE formats could be divided into two groups - those that formed close, ~13 nm contacts between the T cells and cancer cells (Formats A and B), and those that formed larger, ~18 nm gaps (Formats C and D).
They showed that the close-contact forming TcEs (A and B) were better able to recruit and activate the CD2-CD58 co-stimulatory receptor pathway, which provides an important signal to enhance T cell killing. In contrast, the far-contact formats (C and D) were less effective at engaging this co-stimulatory pathway.
Modelling of one of the more flexible T cell engagers
The team also found that the flexibility of the TcE-antigen complex was an important determinant of potency, with less flexible formats performing better.
‘By combining structural, biophysical, and functional analyses, we were able to identify two key parameters that make similarly important contributions to TcE potency - a short distance between the T cell and cancer cell, and less flexibility of the TcE-antigen complex,’ said Michael.
‘These findings provide important new insights that can guide the design of next-generation TcEs with improved potency and efficacy. This knowledge helps us understand existing clinically approved TcE therapies, as well as providing a design principle for optimizing TcE performance.’