What T cell engagers (TCE) are being developed?

Introduction to T Cell Engagers

T cell engagers (TCEs) represent a cutting‑edge class of immunotherapeutics designed to overcome the limitations of conventional cancer treatments. These engineered proteins harness the cytotoxic potential of a patient’s own T cells by physically bridging T cells to cancer cells. In doing so, T cell engagers facilitate the formation of a potent immunological synapse, enabling re‑directed and polyclonal T cell activation and subsequent tumor cell killing. Modern TCEs are being designed not only to address hematologic malignancies but are increasingly aimed at solid tumors with improved specificity and safety profiles.

Definition and Mechanism of Action

T cell engagers are antibody‑based constructs that simultaneously bind to two different cell surface molecules—one on T cells (typically CD3, a component of the T cell receptor complex) and one on the target tumor cell (a tumor‑associated antigen, or TAA). By bridging these two separate cell types, TCEs trigger a cascade of intracellular signaling events that results in T cell activation, cytotoxic degranulation, and cytokine secretion. In essence, the T cell is “redirected” to kill the cell expressing the tumor antigen, even if the T cell’s natural T‑cell receptor (TCR) specificity is not directed towards that tumor–associated antigen. This mechanism bypasses the need for antigen–MHC presentation and aims to reduce some of the immunosuppressive factors seen in the tumor microenvironment (TME).

Importantly, TCEs work at very low concentrations and are designed to provide rapid anti-tumor effects, a quality that has been validated by clinical agents such as blinatumomab—a bispecific construct targeting CD19 and CD3 in B‑cell leukemia. In doing so, these molecules create what is often described as an “immune synapse”—a specialized zone at the interface between T cells and tumor cells—promoting efficient cytotoxic release of perforin, granzymes and other molecules necessary for tumor cell lysis. Their design allows for “off‑the‑shelf” usage without the need for ex vivo manipulation, distinguishing them from cell‑based therapies such as CAR‑T cells.

Historical Development of TCEs

The concept behind redirecting T cell cytotoxicity dates back several decades. Early efforts in immunotherapy capitalized on non‑specific immune activation (for example, with bacterial toxins) before evolving into antibody‑mediated targeting. In the mid‑1980s and early 1990s, preclinical models demonstrated that linking a T cell–binding domain to a tumor‑specific antibody fragment could redirect T cells to kill cancer cells. However, it was not until the advent of bispecific antibody engineering technologies (including tandem single‑chain variable fragments or BiTEs) that TCEs became a realistic therapeutic modality—culminating in the clinical success of agents like blinatumomab, approved for acute lymphoblastic leukemia. Since that time, the field has expanded, and several generations of TCEs have been developed with improved potency, pharmacokinetics and safety profiles. Advances in antibody engineering, display technologies, and computational modeling have all contributed to a rapid evolution from early bispecific designs to more sophisticated trispecific and multispecific formats.

Types of T Cell Engagers

Given the rapid progress in antibody engineering, T cell engagers come in several formats with distinct architectures and pharmacological properties. The two main categories are bispecific T cell engagers, which engage two targets, and trispecific or multispecific engagers, which add additional binding arms to enhance specificity or costimulatory effects.

Bispecific T Cell Engagers

Bispecific T cell engagers (BiTEs) remain the most widely studied class of TCEs. These agents typically combine:

• One antibody fragment that binds CD3 on T cells
• One antibody fragment that binds a tumor‑associated antigen (TAA) on the target cell

A prominent example is blinatumomab, which engages CD19 on B cells and CD3 on T cells. Its success in hematological malignancies paves the way for the concept behind other bispecific constructs. Other bispecific formats are being designed to target solid tumor-associated antigens such as mesothelin, PSMA, HER2, and even peptide‑MHC complexes. The key benefit of bispecific TCEs is their ability to bypass the specificity limitations of the endogenous TCR system and facilitate potent cell‑to‑cell tumor killing even when target antigen expression is low.

In recent literature, there are multiple reports on bispecific TCEs being developed for targets not only on blood‑borne tumors but also for solid tumors, with a focus on minimizing on‑target off‑tumor toxicities. Researchers are investigating variable‐affinity domains and domain order optimization to fine-tune the balance between potency and safety. Furthermore, modifications such as half‑life extension strategies (for example, through Fc engineering) have been employed to allow for more convenient dosing regimens than the continuous infusion approaches typically required for first‑generation BiTEs.

Trispecific and Multispecific Engagers

To overcome some of the limitations inherent to bispecific formats—such as suboptimal T cell activation, toxicity, and limited tumor selectivity—a new generation of trispecific T cell engagers has emerged. These agents incorporate an additional binding moiety that can serve multiple functions:

• Enhancing tumor selectivity by requiring simultaneous engagement of two tumor antigens (logic-gated targeting)
• Providing an additional costimulatory signal, such as engaging CD28 along with CD3, to boost T cell activation and persistence
• Improving overall binding avidity and pharmacological properties

A notable example of a trispecific design is described by work from Sanofi, where a construct targets CD38, CD3, and CD28 simultaneously. In this construct, the CD38 binding domain directs the T cell to the tumor (e.g., multiple myeloma cells), while the coordinated engagement of both CD3 and the costimulatory receptor CD28 overcomes T cell exhaustion and maintains robust T cell proliferation. The trispecific format not only promises enhanced cytolytic activity but also has the potential to offset disadvantages seen with strong CD3 binding affinity that might drive excessive cytokine release syndrome (CRS).

Other multispecific formats may also incorporate additional binding or costimulatory elements, or even include cytokine moieties that help recruit other immune cells such as natural killer (NK) cells. For example, certain designs lead to constructs like TriTACs (Tri‑specific T cell Activating Constructs) from Harpoon Therapeutics, which are designed with multiple binding sites and prodrug “masking” to improve tumor targeting and minimize systemic cytokine release. Moreover, some preclinical advances focus on “logic‑gated” TCEs that only fully activate T cells when two different tumor markers are co-expressed, thereby enhancing tumor selectivity while reducing toxicity from recognition of normal tissues.

Current Development Landscape

The field of T cell engagers is characterized by rapid innovation and a growing portfolio of candidates progressing through preclinical and clinical phases. The current landscape features contributions from both established biopharmaceutical companies and research institutions.

Leading Companies and Research Institutions

Several leading companies have become prominent in the TCE development space. For instance:

• Harpoon Therapeutics has been a pioneer with its proprietary TriTAC platform, which is being leveraged to target a variety of antigens in solid tumors and hematologic malignancies. Harpoon’s pipeline includes candidates targeting PSMA, mesothelin, BCMA, and DLL3, with clinical trials already underway.
• AbCellera is another key player, which recently expanded its collaboration with AbbVie to discover novel T cell engagers for oncology indications. AbCellera’s platform focuses on discovering CD3-binding antibodies with optimized functional attributes that improve the therapeutic window of TCEs.
• Medigene has been active in developing TCR-guided T cell engagers that target intracellular antigens presented by peptide-HLA complexes, thus broadening the antigen repertoire for targeting solid tumors.

On the academic front, numerous research institutions continue to contribute to the understanding of TCE mechanisms and design strategies. The rapid progress in computational modeling studies and mechanistic evaluations—for example, those investigating three-body binding kinetics and the optimal interdomain spacing—has been essential for refining TCE design. These collaborations between industry, academia, and clinical research facilities are critical to moving next-generation T cell engagers forward.

TCEs in Clinical Trials

Many TCE candidates are advancing through clinical trials. For hematologic indications, blinatumomab remains the trailblazer, while new bispecific TCEs targeting antigens such as BCMA are in mid‑to‑late phase clinical trials for multiple myeloma. In solid tumors, early phase studies are ongoing with TCEs directed against targets like HER3, mesothelin, and DLL3. The use of trispecific T cell engagers is also being actively explored in clinical settings, as they offer the promise of robustness with improved safety by providing additional costimulatory signals (for example, the CD38/CD3 × CD28 trispecific antibody in multiple myeloma).

Clinical researchers are exploring various dosing strategies and adaptive trial designs to optimize the balance of efficacy and safety. With continued interest in managing adverse events such as cytokine release syndrome, manufacturers are exploring both molecular modifications (like using medium-affinity CD3 binders) and innovative delivery routes (such as subcutaneous administration). Despite challenges, the clinical data emerging from these early trials highlight the broad potential of TCEs across multiple cancer types, including those previously considered “non‑immunogenic” or cold tumors.

Mechanisms and Targets

At the heart of T cell engager development is the careful selection of antigen targets and the intricate design of the mechanisms that drive tumor cell recognition and killing.

Common Targets in TCE Development

The tumor antigen targeted by a TCE is critical for ensuring both specificity and clinical efficacy. An ideal TAA should be highly expressed on tumor cells while having minimal expression on normal tissues to avoid on-target off‑tumor toxicity. Among the common targets in current TCE development are:

• CD19: Used in hematologic malignancies, particularly in B‑cell leukemias and lymphomas. Blinatumomab is the archetypal agent targeting CD19 and CD3.
• BCMA (B-cell maturation antigen): A target for multiple myeloma, with several BCMA‑directed TCEs in clinical development showing promising anti‑myeloma activity.
• PSMA (Prostate-specific membrane antigen): Frequently targeted in prostate cancer and other solid tumors with emerging TCE candidates.
• Mesothelin: Targeted in solid tumors such as ovarian and pancreatic cancers; candidates continue to be tested in early phase clinical studies.
• DLL3 (Delta-like ligand 3): Being evaluated for small cell lung cancer and other neuroendocrine tumors.
• HER3 and EGFR Family Members: These targets are particularly relevant in breast and gastric cancers, and innovative constructs are being designed to improve selectivity and reduce toxicity.
• Peptide/MHC Complexes: Recent advancements have facilitated the targeting of intracellular tumor antigens presented on the cell surface with TCR‑mimetic or TCR‑guided TCEs. This expands the targetable repertoire beyond traditional surface antigens.

By leveraging such targets, developers strive to improve tumor selectivity and reduce collateral damage to healthy tissues. Some approaches also involve dual antigen targeting strategies (logic‑gated TCEs) that require co‑expression of two antigens, thus further improving specificity and safety.

Mechanisms of Action in Tumor Targeting

The mechanism of action of T cell engagers is multifactorial. When a TCE engages both CD3 on T cells and a TAA on tumor cells, it brings them into intimate proximity, leading to:

• Crosslinking of the CD3 receptor, which triggers T cell activation and downstream signaling cascades.
• Formation of an immunological synapse where cytotoxic granules are released to induce apoptosis in the tumor cell.
• Activation of multiple T cells (even those with low intrinsic specificity for the tumor antigen) to overcome low antigen density on the target cells.
• In the case of trispecific constructs, incorporation of costimulatory signals (e.g., through CD28 engagement) further enhances T cell proliferation and sustains the cytotoxic response, thereby potentially improving in vivo persistence and tumor clearance.

In some designs, additional domains are engineered to incorporate cytokine signals or to “mask” the CD3‑engaging element until the engager reaches the tumor microenvironment—this prodrug approach is aimed at reducing systemic toxicity and off‑tumor activation. Moreover, computational modeling studies have been widely used to identify the optimal interdomain spacing and binding affinities to maximize tumor cell clustering and effective T cell activation. This mechanistic insight informs not only safety and efficacy but also the dosing strategies employed in clinical development.

Challenges and Future Directions

Despite the promising advances in TCE development, several challenges remain. These challenges concern both the molecular design of TCEs and the broader clinical development issues related to safety, efficacy, and manufacturability.

Current Challenges in TCE Development

One of the central challenges in TCE development is balancing potency with safety. High‑affinity CD3 binders, while effective for rapid T cell activation, may also trigger excessive cytokine release syndrome (CRS) and neurotoxicity. This has led researchers to explore the use of attenuated or medium‑affinity CD3 binding domains, as well as engineered delivery mechanisms (e.g., subcutaneous administration) to modulate systemic exposure.

Another critical challenge is the narrow therapeutic window in solid tumors. Unlike hematologic malignancies, many solid tumors express tumor‑associated antigens that are shared with normal tissues. On‑target off‑tumor toxicities are a significant concern in these scenarios. To address this, novel approaches such as dual antigen recognition (logic‑gated assessments) are being developed. These approaches ensure that T cells are only activated when two specific antigens, typically co‑expressed on tumor cells, are recognized simultaneously, thereby sparing normal tissues.

Pharmacokinetics also pose challenges. Early designs of TCEs had short half‑lives necessitating continuous infusion. Newer formats inspired by IgG‑like structures and Fc engineering aim to extend the half‑life, reduce dosing frequency, and improve the overall treatment convenience.

From a manufacturing standpoint, ensuring consistency and scalability of these complex biologics is non‑trivial. The use of multispecific formats, including the incorporation of additional binding domains, increases molecular complexity and can challenge current production technologies. Addressing developability concerns—including issues of aggregation, stability and immunogenicity—is therefore critical for successful clinical translation.

Future Research and Development Trends

Looking ahead, the future of TCE development is being shaped by an array of innovative strategies that aim to overcome current limitations:

• Improved Molecular Designs: Next-generation TCEs are expected to feature optimized binding affinities and domain configurations that maximize power while minimizing adverse events. Advances in computational modeling and protein engineering are playing a key role in fine-tuning these attributes.
• Trispecific and Multispecific Approaches: Incorporating additional antigen or costimulatory binding sites is a main trend. For example, trispecific antibodies that co-engage CD3 and a second T cell costimulatory receptor (such as CD28) with a tumor antigen have demonstrated enhanced efficacy in preclinical models and are expected to proceed into clinical testing.
• Prodrug Strategies and Conditional Activation: Efforts are being made to develop TCEs that remain inactive during systemic circulation and are only activated upon reaching the TME, thereby reducing off-tumor toxicities. ProTriTAC and similar constructs exemplify these strategies.
• Integration with Other Modalities: Future TCEs may be used in combination with checkpoint inhibitors, adoptive cell therapies (including CAR‑T and TCR‑engineered T cells) or other immunomodulatory agents. This combinatorial approach could address mechanisms of treatment resistance and boost overall therapeutic responses.
• Targeting Novel Antigens and Expanding Indications: Broadening the target landscape to include intracellular antigens via peptide/MHC complexes or dual-antigen targeting will pave the way for treating solid tumors that are less immunogenic. This expansion is critical given that many solid tumors lack a single highly specific antigen.
• Advanced Clinical Trial Designs: Novel adaptive trial designs and model‑informed drug development (MIDD) approaches are being incorporated to fine-tune dosing and mitigate risks during early clinical evaluation. This can accelerate development timelines and generate robust safety and efficacy data.
• Manufacturing and Quality Control Innovations: As the technology matures, improvements in expression systems, purification strategies, and analytical methods will be paramount to bringing more complex TCEs from the bench to the bedside at scale.

Conclusion

In summary, the ongoing development of T cell engagers has evolved from early bispecific formats—pioneered by agents like blinatumomab—to advanced constructs that now include trispecific and multispecific designs. Today’s TCEs are engineered to bridge T cells with tumor cells via CD3 and specific tumor-associated antigens, triggering potent cytotoxic responses. In hematologic malignancies, CD19 and BCMA have been validated as effective targets, whereas in solid tumors, innovative targets such as mesothelin, PSMA, DLL3, HER3, EGFR and even peptide‑MHC complexes are being explored to overcome the issues of antigen selectivity and off‑tumor toxicity.

The current development landscape is vibrant—driven by industry leaders like Harpoon Therapeutics, AbCellera, and Medigene, and supported by academic breakthroughs in computational simulations and mechanistic studies. Despite the challenges of toxicity (notably CRS), limited half‑life, and manufacturing complexities, next‑generation TCEs are poised to offer significant improvements in safety and efficacy through strategies such as dual‑antigen targeting, conditional activation, and incorporation of costimulatory domains.

From a mechanistic perspective, TCEs work by forming an immunological synapse that enables efficient tumor cell killing. In addition, trispecific formats that incorporate additional signals like CD28 enhance prolonged T cell activation and offer improved tumor clearance while aiming for narrower therapeutic windows that better differentiate tumor cells from normal tissues. On the horizon, many innovative trends are emerging that include combination treatment regimens and improved protein-engineering methods to overcome current limitations.

In conclusion, the field of T cell engager development is multifaceted and rapidly evolving. Researchers are exploring a broad spectrum of molecular formats—from conventional bispecific TCEs to innovative trispecific antibodies and logic‑gated multispecific engagers—in order to harness and direct the power of T cells with greater precision and safety. Given the significant preclinical and early clinical successes, it is anticipated that these advances will lead to new, effective immunotherapies for a range of cancers, addressing both hematologic malignancies and solid tumors. Future efforts must continue to optimize binding affinities, enhance pharmacokinetic properties, and integrate combinatorial approaches while ensuring manufacturability and safety. The promising data from leading institutions and pioneering companies underscore the transformative potential of the next generation of TCEs, making them a cornerstone of future cancer immunotherapy.