Your 1st-Grade Teacher Was Wrong: BiTEs Have Benefits
FRAMINGTON, MA — Since their introduction in the late 1980s, therapeutic monoclonal antibodies have transformed cancer care at the VA and elsewhere, offering clinicians highly specific tools to target malignant cells while sparing normal tissue. The introduction of bispecific antibodies a decade ago offered more targeted therapies.
The growing number of bispecific T-cell engagers (BiTEs) have further increased the efficacy of immunotherapy against a range of hematologic malignancies as well as some challenging solid tumors such as small cell lung cancer, treated with tarlatamab, and uveal melanoma, for which tebentafusp is an approved therapy.
Bispecific Antibodies and BiTE TherapiesInformation derived from: The Antibody Society. Therapeutic monoclonal antibodies approved or in review in the EU or US. Accessed Dec. 15, 2025.
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For veterans treated through the VA, striking the right balance between effective treatment and potential toxicity raises particular concerns. The aging of veterans who served in Vietnam and Korea has steadily raised the average age of those receiving care at the VA, with more than half of these veterans now over age 65 and one-third over age 75. Further, most have multiple comorbidities that complicate treatment and may make toxicity more difficult to manage.
Early approvals of monoclonal antibodies directed against immune and tumor-associated antigens established mechanisms such as complement-dependent cytotoxicity, antibody-dependent cellular cytotoxicity, and antibody-dependent cellular phagocytosis as central to antibody-based cancer therapy. However, achieving long-term disease control has remained challenging due to resistance mechanisms that enable evasion and facilitate tumor progression.1
While combining monoclonal antibodies with other therapies targeting different receptors or epitopes improves efficacy and durability of response, this approach also increases the risk of toxicity, making them less suitable for many veterans.
An alternative approach has proved successful: bispecific antibodies and their derivatives, bispecific T-cell engagers.
Bispecific Antibodies More Than Double the Impact
Bispecific antibodies bind two distinct antigens or epitopes simultaneously. Unlike conventional monoclonal antibodies, which recognize a single target, bispecifics introduce dual specificity that enables a range of therapeutic strategies while providing greater precision in targeting and, consequently, reduced off-target impact. Bispecifics offer notable targeting flexibility, such as blocking two signaling pathways at once or targeting two disease mediators. They can also transport drugs to specific cells and locations.2
Perhaps their greatest differentiator is the ability of bispecific antibodies to move cytotoxic immune cells within range of cancer cells to facilitate a targeted immune attack. By engaging multiple targets within a single molecule, bispecific antibodies may also help overcome resistance mechanisms that limit the durability of single-target therapies for treating complex malignancies.
To date, 15 bispecific antibodies have received FDA approval. While most have addressed hematologic malignancies, others treat genetic disorders. Notably, just two bispecific antibodies have been approved for treatment of solid tumors—tarlatamab for small cell lung cancer, which received FDA approval in 2024, and tebentafusp approved for uveal melanoma in 2025.
The Antibody Society, based in Framington, MA, maintains a comprehensive list of approved antibody therapeutics and those in regulatory review in the European Union (EU) or United States.
Bispecifics with a singular focus: BiTEs
Bispecific T-cell engagers (BiTEs) represent a specialized subset of bispecific antibodies that play a crucial role in cancer treatment by targeting cancer cells through multiple mechanisms, including simultaneous blockade of signaling pathways and immune cell recruitment.
This targeted immuno-oncology platform connects patients’ own T-cells to malignant cells through a unique structural design: one binding site targets a specific antigen found on cancer cells, while another binds to CD3 receptors on T-cells. This structure allows the antibodies to create a direct bridge between T-cells and cancer cells, streamlining the pathway for elimination.3
Bispecific T-cell engagers differ substantially in structure and mechanisms of action from other bispecific antibodies. Consisting of two single-chain variable fragments and lacking the Fc region found in full-length antibodies, BiTEs are more compact and optimized for direct interaction with immune cells.
Bispecific T-cell engagers offer several advantages over other bispecific antibodies and monoclonal IgG antibodies. They are highly diffusible and can rapidly travel from the administration site to the tumor site, where they effectively redirect cytotoxic T-cells to target cancer cells. Additionally, these agents demonstrate significantly greater efficacy in tumor cell lysis, even with a lower ratio of T-cells to tumor cells.
Like other immunotherapies, BiTE therapy may cause side effects including cytokine release syndrome (CRS); neurological symptoms such as headaches, confusion, dizziness, seizures, and aphasia; hematologic toxicity including neutropenia and thrombocytopenia; gastrointestinal symptoms; fatigue; and increased infection risk.
CRS is the chief concern with bispecific antibodies, but the risk is front loaded. “Over 90% of CRS events occur within the first month,” and are uncommon once a therapeutic dose is achieved, Andrew Ip, MD, a hematologist with the Hackensack University Medical Center, told U.S. Medicine during the 2024 Association of VA Hematology/Oncology (AVAHO) annual meeting.
Side effects can typically be managed with careful monitoring, early detection, and supportive treatments, including corticosteroids and other immunosuppressive drugs.
Looking Ahead
The BiTE platform continues to evolve, with current investigations focused on expanding tumor targets, including antigens expressed in solid tumors. These have posed more challenges arising from tumor microenvironment and immune suppression than are seen in hematological malignancies. BiTEs also are being investigated as possible treatments for two especially hard-to-treat solid cancers, neuroblastoma and pancreatic cancer.
In addition, advances in molecular engineering aim to reduce toxicity by fine-tuning T-cell activation strength and improving target specificity. Other recent advances include enhanced molecular stability to extend drug exposure, optimized delivery strategies to reduce dosing frequency and combination approaches that pair BiTEs with other immunotherapies to achieve synergistic immune activation. Novel multispecific formats, including tri-specific antibodies, are also under investigation to shut down additional tumor escape mechanisms.
- Zahavi D, Weiner L. Monoclonal Antibodies in Cancer Therapy. Antibodies (Basel). 2020 Jul 20;9(3):34. doi: 10.3390/antib9030034. PMID: 32698317; PMCID: PMC7551545.
- Herrera M, Pretelli G, Desai J, Garralda E, Siu LL, Steiner TM, Au L. Bispecific antibodies: advancing precision oncology. Trends Cancer. 2024 Oct;10(10):893-919. doi: 10.1016/j.trecan.2024.07.002. Epub 2024 Aug 30. PMID: 39214782.
- Einsele H, Borghaei H, Orlowski RZ, Subklewe M, Roboz GJ, Zugmaier G, Kufer P, Iskander K, Kantarjian HM. The BiTE (bispecific T-cell engager) platform: Development and future potential of a targeted immuno-oncology therapy across tumor types. Cancer. 2020 Jul 15;126(14):3192-3201. doi: 10.1002/cncr.32909. Epub 2020 May 13. PMID: 32401342.