What are the different types of drugs available for T cell engagers (TCE)?

Introduction to T Cell Engagers

Definition and Mechanism of Action
T cell engagers (TCEs) are a class of engineered immunotherapeutics designed to bridge two distinct cellular targets: cytotoxic T cells and tumor cells. They achieve this by exploiting the natural cytolytic function of T cells, effectively “redirecting” them toward cancerous cells. The fundamental mode of action involves binding simultaneously to an antigen expressed on the tumor cell and to CD3 on T cells. This dual engagement results in the formation of an artificial immunological synapse that triggers T cell activation, proliferation, cytokine release, and ultimately the lysis or killing of the tumor cell. The molecular design and spatial orientation of the binding domains in TCEs are critical because they determine how efficiently the T cell is activated upon encountering its target.

TCEs harness both biochemical and biophysical principles. Mechanistically, when a TCE binds to the target antigen and the CD3 receptor, it bypasses the conventional major histocompatibility complex (MHC)-restricted antigen recognition system, allowing for rapid and potent cytotoxicity even in tumors with low antigen density. In some designs, the affinity of the CD3-binding moiety is deliberately fine-tuned so that T cell activation remains submaximal at baseline but becomes highly effective upon simultaneous tumor antigen binding. This precision in engaging T cells helps to minimize non-specific activation, thereby reducing widespread systemic toxicity, such as cytokine release syndrome.

Role in Cancer Immunotherapy
In the landscape of cancer immunotherapy, T cell engagers represent a revolutionary approach that capitalizes on the patient’s own immune system to fight malignancy. Their role is particularly pronounced in hematological cancers where the targets are often highly expressed on the surface of tumor cells, but their use is rapidly expanding into solid tumors with advances in engineering and targeting strategies. Unlike broad-acting immunotherapies such as checkpoint inhibitors, TCEs are designed to achieve high specificity by simultaneously engaging T cells and specific tumor-associated antigens (TAAs); this selective redirection enhances the tumor-killing potential while sparing healthy tissues.

Furthermore, T cell engagers are “off-the-shelf” therapies that can be administered repeatedly in a clinical setting without the need for personalized cell manufacturing, as is the case with chimeric antigen receptor (CAR) T cell therapies. Their modular design provides flexibility to target different cancers by simply swapping the tumor-binding domain. The advent of these engineered proteins has spurred the development of varied formats that extend the range of cancers that can be treated, including hematological malignancies such as acute lymphoblastic leukemia and non-Hodgkin lymphomas, as well as challenging solid tumors.

Types of T Cell Engager Drugs

T cell engagers can be broadly classified into several categories. These variances are based on molecular structure, mode of action, and the delivery platform. Below, we delineate the primary types of drugs available in this field.

Bispecific Antibodies
Bispecific antibodies (bsAbs) represent one of the most common and well-studied classes of T cell engagers. These molecules are engineered to contain two distinct antigen-binding sites. One arm is specific to a tumor-associated antigen (TAA), while the other binds to the CD3 complex on T cells, effectively bridging the immune effector cell to the tumor cell.

Key characteristics of bispecific antibodies include:
- Structure and Format:
The earliest designs, such as the bispecific T cell engager (BiTE) format, are typically composed of two single-chain variable fragments (scFvs) connected by a short flexible linker, forming a compact molecule. Owing to their small size and high potency, BiTEs such as blinatumomab require continuous infusion due to a short serum half-life. Recent advances have led to extended half-life versions by including an Fc domain or using alternative linker strategies to improve stability and dosing convenience.
- Multispecific and Logic‐Gated Designs:
Advances in antibody engineering have enabled constructs that are not strictly bispecific. Trispecific antibodies, for example, incorporate a third binding domain that can either target an additional tumor antigen or provide a co-stimulatory signal via receptors such as CD28. This design may increase tumor selectivity and reduce immune escape by requiring simultaneous engagement of multiple cell surface markers. In addition, logic-gated dual targeting, where two distinct tumor antigens must be recognized in tandem to induce T cell activation, has been explored as a way to mitigate on-target off-tumor toxicity.
- Platform Technologies:
Companies like AbCellera have developed complete T cell engager platforms that include libraries of fully human, developable CD3-binding antibodies characterized by unique binding and functional properties. Such advances ensure that the resulting bispecific antibody not only possesses high specificity for its targets but also optimal biophysical characteristics, such as solubility and stability, which are crucial for clinical success.

Bispecific antibodies continue to be a dominant modality in clinical trials, with over 100 candidates already being evaluated in various stages, indicative of the rapid pace of innovation in this domain.

CAR-T Cells
Chimeric Antigen Receptor (CAR)-T cells represent another revolutionary category of T cell engager drugs. Although they differ fundamentally from soluble bispecific antibodies, they function with the same underlying principle of redirecting T cell cytotoxicity toward tumor cells.

Key aspects of CAR-T cell therapies include:
- Cell-based Therapy Approach:
Unlike bispecific antibodies that are recombinant proteins, CAR-T therapies involve the ex vivo genetic modification of a patient’s T cells to express a receptor that combines an extracellular antigen recognition domain (typically derived from an antibody’s scFv) with intracellular signaling domains that promote T cell activation and persistence. This allows for efficient killing of tumor cells upon re-infusion into the patient.
- Generational Evolution:
CAR-T cell constructs have evolved over multiple generations. First-generation CARs comprised only the CD3ζ signaling domain, providing activation but limited persistence and expansion. In subsequent generations, co-stimulatory domains such as CD28, 4-1BB, or others have been incorporated to enhance proliferative capacity, persistence, and memory T cell formation. These refinements have led to marked improvements in clinical outcomes, particularly in hematological malignancies.
- Expanded Specificity and Safety Modifications:
The versatility of CAR-T cell therapy is further demonstrated by the development of T cells that express dual or even trispecific receptors. Engineering strategies now include incorporating safety switches, suicide genes, or tunable co-stimulatory signals to mitigate on-target off-tumor toxicities and cytokine release syndrome. Furthermore, alternative targeting strategies such as transgenic T cell receptor (TCR) T cells are being explored to address limitations in antigen recognition in solid tumors.

CAR-T cell therapies are highly personalized, as they require the extraction, modification, and expansion of autologous T cells. Despite the complexity of manufacturing, the clinical successes of CAR-T cells in treating B-cell malignancies have established them as a critical component of the T cell engager arsenal.

Other Novel Approaches
In addition to classical bispecific antibodies and CAR-T cells, several emerging strategies are being developed to further improve the targeting, efficacy, and safety profiles of T cell engagers. These include:

- Multispecific Engagement Technologies:
Recent research is exploring trispecific or even multispecific antibody constructs that allow for simultaneous engagement of more than two antigens. Examples include trispecific killer engagers (TriKEs) that not only target tumor cells but also incorporate an interleukin-15 (IL-15) moiety to enhance natural killer (NK) cell activation and proliferation. These trispecific constructs can improve immune-cell engagement by providing an “all-in-one” platform to boost the cytotoxic function while increasing specificity.
- Prodrug T Cell Engagers:
Novel platforms, such as the ProTriTAC™ developed by Harpoon Therapeutics, apply a prodrug concept to T cell engager design. In these constructs, the T cell engager remains inactive until reaching the tumor microenvironment, reducing systemic exposure and toxicity such as cytokine release syndrome. This conditional activation ensures that T cells are only unleashed in the vicinity of the tumor, enhancing the therapeutic window.
- Nanobody-Based and Peptide-Modified Engagers:
Some innovative approaches involve the creation of multispecific nanobodies or the use of peptide modifications to improve half-life and targeting precision. These modifications can be applied to create bispecific or trispecific constructs with improved distribution, tissue penetration, and safety profiles. For example, patents describe compositions where T cell engagers are modified with peptides and half-life extending molecules to allow for better pharmacokinetics and reduced off-target effects.
- Regulatory T Cell (Treg) Targeting and Immune Modulatory Strategies:
Beyond direct T cell redirection, some novel modalities aim to modulate the immune microenvironment by engaging regulatory pathways. For instance, strategies to selectively target T cell subsets such as Vγ9Vδ2 T cells through bispecific constructs have shown the potential to combine innate antitumor activity with adaptive immune cytotoxicity. This level of sophistication adds an extra layer of control over T cell activity, tailoring responses to the unique tumor microenvironment.

Collectively, these emerging approaches reflect the continuous innovation in the T cell engager field, with an emphasis on enhancing tumor selectivity, minimizing systemic toxicities, and expanding the range of treatable cancers.

Current Market and Development Pipeline

Approved T Cell Engager Drugs
The clinical landscape of T cell engagers has expanded significantly over the past decade, with demonstrable success leading to regulatory approvals. One notable example is blinatumomab, a bispecific T cell engager (BiTE) approved for the treatment of relapsed/refractory B-cell precursor acute lymphoblastic leukemia. Blinatumomab was one of the first drugs to validate the therapeutic concept of redirecting T cell cytotoxicity through simultaneous binding to CD19 on tumor cells and CD3 on T cells. More recently, other T cell engager drugs, such as tebentafusp—which uniquely targets a gp100 peptide presented in the context of HLA-A*02:01—and others in similar innovative formats, have been approved or are in late-stage development. Each of these approvals underscores the efficacy of the concept in hematological as well as some solid tumor indications, albeit with different safety and administration profiles.

Drugs in Clinical Trials
In parallel to the approved agents, a robust pipeline of T cell engagers is under active clinical investigation. Over 100 bispecific T cell engager candidates are currently in early to late-phase clinical trials across multiple cancer indications, reflecting the transformative potential of this modality in oncology. These clinical trials are not limited to hematological malignancies but have expanded to address the challenges of treating solid tumors. For example, Phase 1 and Phase 2 studies are evaluating next-generation formats such as extended half-life bispecific constructs that reduce the frequency of administration and improve safety via conditional activation.

Additionally, clinical trials are exploring combination strategies where T cell engager therapy is combined with checkpoint inhibitors, cytokine modulators or other targeted therapies to synergize antitumor effects while attenuating adverse events. The extensive clinical pipeline is characterized by a diversity of formats, from traditional BiTEs to multi-specific engagers and advanced cell therapies like CAR-T cells engineered for solid tumor infiltration.

Innovative trial designs, such as the dose intra-subject escalation to an event (DIETE) method, are being implemented to better define dosing parameters that can maximize efficacy while minimizing toxicity for TCE drugs. This trend in clinical trial innovation reflects an evolving understanding of the pharmacodynamics and pharmacokinetics of these complex biologics and cell therapies.

Challenges and Future Directions

Clinical Challenges and Limitations
Despite the impressive advances and promising clinical results, T cell engagers face several inherent challenges. One of the major obstacles is the risk of systemic toxicities, most notably cytokine release syndrome (CRS) and neurotoxicity, which arise from excessive immune activation. CRS, in particular, is a significant concern because even small variations in the dosing regimen can lead to severe adverse events. This has prompted the use of strategies such as step-up dosing and the development of constructs with extended half-life properties that allow for controlled activation.

Another clinical challenge is the potential for on-target off-tumor toxicity. Because many tumor-associated antigens are also expressed at low levels in healthy tissues, there is a risk that T cell engagers might inadvertently target normal cells, leading to significant adverse outcomes. Logic-gated designs and dual targeting strategies have been introduced to enhance selectivity, but these approaches require further refinement.

The complexity of manufacturing, especially for cell-based therapies such as CAR-T cells, also poses logistical and economic challenges. Customized manufacturing processes, quality control issues, and the need for rapid turnaround times are critical factors that can affect widespread adoption and affordability. Additionally, the heterogeneity in patient tumor antigen expression and the dynamic nature of the tumor microenvironment further complicate dosing strategies and therapeutic efficacy.

Future Research and Development
Future directions in T cell engager development are geared toward addressing these challenges. Advances in molecular engineering are expected to yield next-generation TCEs that combine improved pharmacokinetic profiles with enhanced specificity. This includes the development of multi-specific constructs that require the simultaneous engagement of two or more tumor antigens, thereby reducing off-target effects.

On the cell therapy front, innovations in CAR-T cell design continue to evolve. The integration of safety switches, dual- or trispecific receptors, and modifications that allow for modulation of co-stimulation are areas of active research. These innovations aim not only at improving efficacy but also at reducing adverse events and facilitating treatment in more complex tumor environments such as solid tumors. Moreover, the growing use of artificial intelligence and machine learning in drug discovery and clinical trial design is expected to optimize patient selection and dosing protocols through better biomarker integration and real-time monitoring.

Research is also emphasizing the need to modulate the tumor microenvironment to enhance T cell penetration and functionality. Approaches such as combined checkpoint blockade, immunomodulatory cytokine delivery, or even mechanical engineering of the T cell surface are under investigation to improve T cell migration and activity within the dense tumor stroma.

Furthermore, the use of prodrug T cell engagers that remain inactive until reaching the tumor site represents a promising strategy to minimize systemic exposure and reduce toxicities. This strategy, exemplified by the ProTriTAC platform, could pave the way for safer treatments while maintaining the potent antitumor effects of T cell engagers.

In terms of regulatory science, integrated model-informed drug development (MIDD) strategies are being employed in clinical trials to optimize dose selection and scheduling. These strategies enable the simulation of different dosing regimens and help predict the therapeutic window, thereby reducing the risk in early-phase trials. Collaborations across industry, academia, and regulatory bodies are key to advancing these novel agents to market while ensuring patient safety.

Conclusion
In summary, T cell engagers represent a highly dynamic and rapidly advancing field in cancer immunotherapy. They are engineered drugs that work by redirecting the natural cytotoxic potential of T cells toward tumor cells through simultaneous binding to CD3 on T cells and specific tumor-associated antigens. The field comprises a diversity of drug types including bispecific antibodies, CAR-T cell therapies, and other novel approaches such as trispecific constructs and prodrug platforms. Bispecific antibodies such as BiTEs have demonstrated impressive antitumor activity, exemplified by the approval of blinatumomab, while CAR-T cell therapies have shown transformative clinical success in hematological malignancies. Meanwhile, emerging technologies including multispecific and prodrug T cell engagers hold promise for overcoming current challenges such as cytokine release syndrome, on-target off-tumor toxicity, and manufacturing complexities.

The current market features approved drugs and a robust clinical pipeline with over 100 candidates in various stages of investigation, covering both hematological and solid tumors. However, significant clinical challenges remain, particularly related to toxicity and the need for precise dosing strategies. Future research will focus on improving molecular designs, developing innovative dosing strategies, and employing combination regimens to enhance efficacy while mitigating risks.

Ultimately, the advancements in T cell engager technology are transforming cancer treatment by offering more targeted, potent, and safer immunotherapies. Continuous innovation, guided by detailed clinical pharmacology insights and rigorous biomarker integration, will likely expand the therapeutic potential of T cell engagers across a broader range of malignancies, heralding a new era in precision immunotherapy.