Immunotherapy is one of medicine’s most promising frontiers in cancer treatment by ingeniously transforming patients’ own immune systems into personalized cancer-fighting arsenals. By eliminating malignant cells while sparing healthy tissues, this type of treatment achieves potency and precision — the twin pillars of successful cancer treatment.
While the initial wave of immunotherapies has already revolutionized oncology, a remarkable innovation is now emerging: Bi-specific T cell engagers (Bi-TCEs). These engineered proteins represent perhaps the most elegant solution yet — molecular bridges that physically force cancer cells and immune cells together, creating an unavoidable deadly encounter from which cancer cells cannot escape.
Structurally, Bi-TCEs consist of two single-chain variable fragments (scFvs) connected by a flexible linker. One scFv binds to a tumor-associated antigen (TAA), while the other targets CD3, a key component of the T cell receptor complex. This dual specificity enables Bi-TCEs to physically link any CD3-expressing T cells with cancer cells, bypassing the need for peptide-MHC recognition. Upon engagement, Bi-TCEs trigger a potent immunological cascade activating T cells, promoting their proliferation, and inducing the release of perforin and granzymes that mediate tumor cell lysis (see Figure 1). This mechanism of action has proven effective in hematologic malignancies, positioning Bi-TCEs as a promising frontier in cancer immunotherapy.
Bi-specific T cell engagers in the cancer immunotherapy landscape
How do Bi-TCEs compare to the predominant cancer immunotherapy approach, CAR-T? One key difference is their production method — CAR-T therapies are developed by genetically engineering a patient’s own T cells, whereas Bi-TCEs are produced by engineering proteins in antibodies from mammalian cell lines. This makes Bi-TCEs an “off-the-shelf” type of drug that is simpler to produce than individualized CAR-T therapies.
There are other important comparisons, summarized below in Table 1:
Publication trends show increasing opportunities in cancer research and beyond
We examined the CAS Content CollectionTM, the largest human-curated repository of scientific information, to better understand the research landscape of Bi-TCEs. There has been a significant increase in the number of journal and patent documents in the last 10 years. Interestingly, patents hold a 44% share of the total number of documents, suggesting sustained commercial interest in this area (see Figure 2).
We analyzed the patent data to find the top 10 commercial patent assignees (see Figure 3). Amgen was the first to develop a globally approved Bi-TCE molecule in hematology and continues to be the leader in this field with their proprietary BiTE® technology.
We also explored the leading therapeutic areas in the context of Bi-TCEs using the CAS indexed concepts accessed through CAS STNext®. Our landscape analysis shows that the development of Bi-TCEs is predominantly concentrated in solid tumors, with the highest documents on lung, breast, pancreatic, prostate, and ovarian cancers. Hematological malignancies form the second major focus area, driven largely by programs targeting multiple myeloma and acute leukemias (see Figure 4).
In contrast, autoimmune diseases represent a smaller emerging area of exploration, with interest distributed across conditions like rheumatoid arthritis, systemic lupus erythematous, and Sjörgen syndrome. Noteworthy is the majority of FDA-approved Bi-TCEs so far are for hematological indications. However, in our analysis, we see that the number of documents is highest for solid tumors. This is probably due to the increased ongoing efforts to efficiently utilize Bi-TCEs for solid tumor indications.
The first FDA-approved Bi-TCE, blinatumomab, was approved in 2014. It targets CD19 and CD3 and is indicated for relapsed or refractory B-cell acute lymphoblastic leukemia. Many more Bi-TCE therapeutics have gained accelerated approval from FDA since then for various cancer types, including two solid tumor indications. The details are summarized in Table 2 below:
Table 2:Overview of Bi-TCEs approved by FDA (including accelerated approvals, as of November 2025). CD: cluster of differentiation; gp100, glycoprotein 100; HLA-A, human leukocyte antigen-A; BCMA: B-cell maturation antigen; GPRC5D: G-protein coupled receptor family C group 5 member D; DLL3: Delta-like ligand 3, R/R: Relapsed or refractory. Source: U.S. Food and Drug Administration
Limitations of Bi-TCEs as a cancer cure
Bi-TCEs are considered transformative in hematologic cancers but still face several limitations. Classical Bi-TCEs (e.g., BiTEs like blinatumomab) are small antibody fragments (~55 kDa) lacking an Fc domain. This means they are rapidly cleared by renal filtration, resulting in a plasma half-life of only a few hours. Continuous intravenous infusion is required to maintain therapeutic concentrations, which increases the burden on patients and healthcare resources.
Bi-TCEs induce polyclonal T cell activation by crosslinking CD3 with tumor antigens, leading to massive cytokine secretion (IL 6, IFN γ, TNF α) known as cytokine release syndrome (CRS). CRS manifests as fever, hypotension, and multi-organ dysfunction. Bi-TCEs are also associated with a risk of neurotoxicity, specifically an immune effector cell-associated neurotoxicity syndrome (ICANS). These toxicities can be life threatening and require hospitalization, corticosteroids, or IL 6 receptor blockade (e.g., tocilizumab).
Bi-TCEs exhibit strong activity in hematologic malignancies but have shown limited clinical success in solid tumors. Barriers include tumor penetration, antigen heterogeneity, and immunosuppressive microenvironment. Another critical limitation of Bi-TCEs is the on-target, off-tumor toxicity phenomenon. Many tumor-associated antigens (e.g., CD19, BCMA, EpCAM) are also expressed at low levels on normal tissues. Consequently, Bi-TCEs can redirect T cells to attack healthy cells, leading to collateral tissue damage and limiting antigen selection.
Recent developments in cancer research with Bi-TCEs
Recent advances in Bi-TCEs reflect a concerted effort to address the above-mentioned challenges and drive greater clinical impact with these treatments. Ongoing innovations are enhancing their precision, safety, and durability, positioning Bi TCEs as a rapidly evolving class of immunotherapies with expanding potential across diverse cancer types. Some of the most notable approaches include:
Half-life extended Bi-TCEs (HLE Bi-TCEs):
Canonical Bi-TCE molecules have a short half-life of two to four hours due to the absence of an Fc domain, requiring continuous intravenous infusion. To address this, HLE Bi-TCEs are being developed which fuse the Bi-TCE to an Fc domain, enabling FcRn recycling and prolonged circulation. Preclinical and early clinical studies show HLE Bi-TCEs maintain activity with CD19 and BCMA HLE Bi-TCEs achieving half-lives of up to 210 hours, supporting once-weekly dosing.
CD3 tuning and 2:1 formats:
CD3 tuning in Bi-TCEs involves adjusting the affinity of the CD3-binding arm to control T cell activation. Lower-affinity CD3 binding reduces excessive cytokine release while still enabling effective tumor cell killing, thereby improving safety. The 2:1 format places two binding domains for the tumor antigen and one for CD3, increasing tumor selectivity and potency by ensuring stronger engagement with cancer cells before activating T cells. Together, CD3 tuning and the 2:1 format are key engineering strategies to balance efficacy with tolerability in next generation Bi-TCE therapies.
[H3]: Dual-targeting and tri-specific engagers:
To address antigen heterogeneity and escape, researchers are advancing dual- and tri-specific engagers that co-target two tumor antigens to increase specificity and coverage or add a costimulatory arm to boost T cell fitness in immunosuppressive settings. Dual-specific T-cell engagers have two binding sites: one for CD3 on T cells and one for a tumor-associated antigen, forcing immune synapse formation and cytotoxicity. Tri-specific engagers (TriTEs) expand this design with a third binding site, which can target a second tumor antigen to prevent escape or engage a co-stimulatory receptor such as CD28 to enhance T cell activation. This added domain increases selectivity and potency, ensuring stronger tumor recognition before T cell engagement. “AND-gate” approaches that leverage dual tumor antigen targeting are helpful in reducing the on-target, off-tumor toxicity of Bi-TCEs.
Novel delivery systems:
New delivery systems for Bi-TCEs aim to overcome the limitations of short half-life and continuous infusion. AAV-based gene therapy enables in vivo expression of Bi-TCEs, allowing sustained production from the patient’s own cells and potentially supporting single-dose treatment. Additionally, other approaches like extracellular vesicles are being explored to deliver Bi-TCEs directly into the tumor microenvironment for enhanced local immune activation.
Other strategies include targeting novel tumor antigens to expand their efficacy in solid tumors. Some Bi-TCEs use microenvironment-mediated activation, binding only under tumor-specific conditions to reduce off-target toxicity. Albumin-binding domains are being added to Bi-TCEs to extend half-life and improve pharmacokinetics by leveraging natural albumin recycling. Bi-TCEs are also being combined with checkpoint inhibitors, cytokines, or cell therapies to enhance immune activation and overcome resistance mechanisms.
Clinical trials suggest future directions for Bi-TCE therapies
We analyzed data from Clinicaltrials.gov for insights on the current landscape of clinical trials in this field. As seen in Figure 5, most trials with status “Active, recruiting” are for well-established and FDA-approved candidates, which dominate the hematological cancer domain (196 trials). A smaller but meaningful proportion is directed toward solid tumors (33 trials) with limited efforts in autoimmune diseases, amyloid light chain amyloidosis (AL amyloidosis), and kidney disorders.
Across indications, the highest concentration of trials is in phase 2 (122), followed by phase 1 (40) and phase 1/2 (30), indicating a clinical pipeline that is maturing but still focused on early- to mid-stage activities. Only a few candidates have reached phase 3 (28 trials), reflecting the challenges of translating T cell redirecting therapies beyond hematological settings.
Our analysis highlights two major trends — strong clinical momentum in B-cell malignancies and a gradual expansion of Bi-TCEs into solid tumors and non-oncology diseases. Some of the phase 3 clinical trials for solid tumors involve approved drugs in combination with other chemotherapy or immune checkpoint inhibitors (e.g., Tebentafusp + Pembrolizumab).
The newer candidates, which the FDA has not approved yet, and their details are summarized in Table 3:
Table 3: Summary of notable Bi-TCE candidates in clinical development. Abbreviations: R/R: Relapsed/Refractory; AML: Acute myeloid leukemia; MDS: Myelodysplastic Syndrome; EpCAM: Epithelial cell adhesion molecule; CLDN6: Claudin-6; FLT3: fms like tyrosine kinase 3; STEAP1: Six transmembrane epithelial antigen of the prostate 1; CDH3: cadherin-3; MSLN: mesothelin; HER2: human epidermal growth factor receptor 2; AAV: Adeno-associated virus.
These new Bi-TCEs have demonstrated considerable potential and favorable results in early clinical studies. They show that the field is rapidly evolving, and the development of next-generation Bi-TCEs aims to enhance efficacy while improving safety profiles.
Bi-TCEs are carving out a crucial niche in oncology treatment and are poised to offer improved outcomes for patients. They may also play an important role in treating conditions other than cancer. As research expands, they could soon drive new breakthroughs and more hope for patients everywhere.
Table 1 References:
Slaney CY, Wang P, Darcy PK, Kershaw MH. CARs versus BiTEs: A Comparison between T Cell-Redirection Strategies for Cancer Treatment. Cancer Discov. 2018 Aug;8(8):924-934. doi: 10.1158/2159-8290.CD-18-0297. Epub 2018 Jul 16. PMID: 30012854.
Edeline, J., Houot, R., Marabelle, A. et al. CAR-T cells and BiTEs in solid tumors: challenges and perspectives. J Hematol Oncol 14, 65 (2021). https://doi.org/10.1186/s13045-021-01067-5
Dalal PJ, Patel NP, Feinstein MJ, Akhter N. Adverse Cardiac Effects of CAR T-Cell Therapy: Characteristics, Surveillance, Management, and Future Research Directions. Technology in Cancer Research & Treatment. 2022;21. doi:10.1177/15330338221132927
