Data-led engineering and platform strategies are transforming T cell engagers into scalable, clinically viable cancer therapies.
By Petra Dieterich, Senior Vice President & Scientific Leader, Thomas Cornell, Senior Manager of Protein Engineering, and Rob Holgate, Vice President of Research & Innovation.
Bispecific T cell engagers (TCEs) represent a new generation of antibody-based immunotherapies that redirect T cells to selectively destroy cancer cells. Offering a compelling balance between the precision of CAR T cell therapy and the scalability of monoclonal antibodies, TCEs are gaining traction as a practical and powerful alternative to conventional approaches.
In this article, experts from Abzena explore how platform-based strategies and data-led molecular engineering are helping developers to overcome the challenges of TCE development. These integrated approaches support faster, safer, and more scalable delivery of next-generation therapies, with the goal of transforming TCEs from emerging tools into frontline treatment options.
A promising shift in cancer immunotherapy
As next-generation immunotherapies assume an increasingly central role in oncology, the market for T cell redirecting agents is rapidly expanding. By mid-2024, nine TCEs had gained regulatory approval, and forecasts estimate the global market will surpass $20 billion by 2030 (1). Unlike CAR T cell therapies, which require patient-specific engineering, TCEs offer a more flexible solution, making them more accessible while maintaining targeted immune activation.
These molecules work by binding both a tumor-associated antigen and a T cell co-receptor, typically CD3 (cluster of differentiation 3). This dual-binding mechanism enables TCEs to form a synthetic immune synapse, directing the body’s own T cells to recognize and eliminate cancer cells. While early versions such as blinatumomab demonstrated clinical promise, they also highlighted the need for better formats with improved stability, manufacturability, and safety (2).
The industry is now focused on addressing these limitations through smarter molecular design and robust development platforms, combining precision engineering with streamlined, scalable processes.
Designing complexity with control
Modern TCEs can be tailored across multiple dimensions: binding affinity, geometry, symmetry, Fc (fragment crystallizable) region inclusion, and chain pairing. All of these properties influence how the molecule behaves in vivo and its manufacturability. Although TCEs provide an alternative to patient-specific therapies, this complexity rules out a one-size-fits-all model as they demand a high degree of molecular customization to ensure optimal efficacy, manufacturability, and safety.
To navigate this, developers are turning to structured matrix-based design strategies. These matrices allow teams to systematically vary format elements, such as homo- versus hetero-dimerization, spatial arrangement of arms, or reformatting of binding domains to evaluate a wide range of construct types in parallel.
This data-led approach reduces risk by focusing only on candidates that balance potency, stability, and manufacturability. The ability to rationally explore and triage formats using this design matrix model supports faster lead selection while ensuring downstream compatibility with scale-up and clinical development processes.
Analytical methods enable informed triaging
Once a matrix of candidate constructs has been generated, a robust analytical pipeline is essential. Early assessments should focus on biophysical properties such as yield, purity, and thermal stability — key indicators of a molecule’s potential for consistent, scalable manufacturing.
However, functional assays are equally critical. T cell activation assays and peripheral blood mononuclear cell (PBMC)-based tumor cell killing models help determine whether candidate molecules engage their targets and induce the desired immune response. These in vitro systems can also enable comparisons against clinically validated therapies like blinatumomab, providing a clear reference point for efficacy.
To de-risk development further, safety screening should be built into early-stage triaging. Whole blood cytokine release assays are used to identify formats that may trigger excessive immune activation, which is critical for mitigating the risk of cytokine release syndrome, a known concern with TCEs.
By combining functional potency with manufacturability and safety profiles, developers can make well-informed decisions about which leads to advance, significantly reducing late-stage failure risk.
Manufacturing-ready design from the outset
As TCE formats evolve toward more complex tri- and tetra-specific designs, early consideration of manufacturability is increasingly important. Structural intricacies increase the chance of mispairing, unwanted by-products, and inconsistent behavior under scale-up conditions.
To manage this, a platform-based development model is essential. Integrating molecular engineering, bioanalytics, and process development allows teams to assess all critical quality attributes early. Platform technologies support the rapid generation and screening of multi-specific constructs, enabling the identification of candidates that are not only effective but also commercially viable.
For example, certain candidate formats have demonstrated strong cancer-killing activity and low cytokine release in screening assays. Equally important, they also demonstrated high yield and purity, along with favorable stability, key metrics that support successful scale-up and clinical manufacturing. By integrating rational design with manufacturability considerations from the outset, this end-to-end approach can help shorten development timelines and reduce production costs.
A forward-looking framework
The promise of TCEs lies in their ability to bridge two therapeutic extremes: the accessibility of chemotherapy and the precision of cell therapy. Their potential to become a first-line treatment option will depend not just on their biological activity but also on how efficiently they can be designed, tested, and manufactured.
As the field expands to include new immune cell targets, multi-specific formats, and novel mechanisms of action, developers will need to adopt flexible, data-driven platforms to keep pace. Contract development and manufacturing organizations with robust development frameworks and integrated expertise across molecular design, analytics, and manufacturing can help oncology developers overcome the complex challenges of TCE development and unlock their full therapeutic potential.
With continued investment in platform technologies and cross-disciplinary expertise, T cell engagers may soon become a foundational component of the oncology treatment landscape.
This article was contributed by Petra Dieterich, SVP & Scientific Leader, Thomas Cornell, Senior Manager of Protein Engineering, and Rob Holgate, VP of Research & Innovation at Abzena.
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