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    Bispecific antibodies and T-cell engagers

    Also known as bispecifics, BiTEs, T-cell engagers, PD-1 x VEGF bispecifics

    Bispecific antibodies bind two targets at once. T-cell engagers such as tarlatamab and teclistamab link T cells to a tumour antigen, while immune bispecifics such as ivonescimab combine PD-1 blockade with VEGF inhibition.[1][2][3] In 2026 they produced several FDA approvals and an overall-survival win against pembrolizumab in lung cancer.[4][3]

    Editor reviewedStrict sourcingUpdated Cancer immunotherapyHealth and medicineLife sciences
    Key facts

    Bispecific antibodies are engineered to grab two different targets. In cancer immunotherapy, two families matter.[1][3] T-cell engagers bind a tumour antigen and CD3 on T cells, pulling the two together. Immune-modulating bispecifics instead fuse checkpoint blockade with a second mechanism, such as VEGF inhibition.[1][5]

    T-cell engagers

    In May 2024 the FDA granted accelerated approval to tarlatamab (Imdelltra), a DLL3 x CD3 T-cell engager, for extensive-stage small cell lung cancer after platinum chemotherapy; 40% of 99 patients responded.[1] The confirmatory DeLLphi-304 trial of 509 patients then showed median overall survival of 13.6 months versus 8.3 months with chemotherapy (hazard ratio 0.60), with fewer severe adverse events.[6] Fewer patients stopped treatment because of side effects: 5% on tarlatamab versus 12% on chemotherapy.[7] In myeloma, the BCMA x CD3 engager teclistamab plus daratumumab was approved in March 2026 after MajesTEC-3 showed a progression-free survival hazard ratio of 0.17.[2] In the NEJM report, estimated 36-month progression-free survival was 83.4% versus 29.7% with standard daratumumab-based regimens. The benefit came with more serious adverse events (70.7% vs 62.4%) and slightly more deaths from adverse events (7.1% vs 5.9%).[8] Epcoritamab gained follicular lymphoma indications in November 2025.[9]

    T-cell engagers are also moving into first-line treatment of children. In a trial of 709 children with newly diagnosed high-risk B-cell acute lymphoblastic leukaemia, published in NEJM in September 2026, two cycles of the CD19 x CD3 engager blinatumomab replaced two cycles of chemotherapy. At a planned interim analysis, estimated 4-year event-free survival was 83.0% versus 70.3% (hazard ratio 0.51). Treatment-related infections were less common (23.9% vs 69.4%), but neurotoxic events were more common (12.0% vs 3.2%).[10]

    Like CAR-T, T-cell engagers can cause cytokine release syndrome and ICANS, which carry boxed warnings on their labels.[11]

    Tumour-targeting bispecifics with checkpoint inhibitors

    Zanidatamab, a bispecific antibody targeting HER2, was approved in August 2026 with the PD-1 inhibitor tislelizumab for first-line HER2-positive gastroesophageal adenocarcinoma, extending median overall survival to 26.4 months versus 19.2 months with trastuzumab.[4]

    PD-1 x VEGF bispecifics

    Ivonescimab binds PD-1 and VEGF. Its developer Akeso reported in September 2026 that in HARMONi-2 it extended median overall survival to 30.8 months versus 22.6 months with pembrolizumab in first-line PD-L1-positive non-small cell lung cancer (hazard ratio 0.73).[3] In HARMONi-6, ivonescimab plus chemotherapy cut the risk of death by 34% versus tislelizumab plus chemotherapy in squamous lung cancer.[12] In the US, Summit Therapeutics filed for approval in EGFR-mutated lung cancer after TKI therapy, with an FDA goal date of 14 November 2026.[13] Large companies have bought in: in June 2025 Bristol Myers Squibb agreed to pay BioNTech $1.5 billion upfront to co-develop the PD-L1 x VEGF-A bispecific BNT327.[5]

    Open questions

    The HARMONi-2 and HARMONi-6 survival results come from company announcements and conference presentations rather than full peer-reviewed papers, and the checkpoint comparators differ between trials.[3][12] The FDA decision due by 14 November 2026 is the next regulatory test for ivonescimab.[13]

    Questions readers ask

    What is a T-cell engager?

    A bispecific antibody that binds a tumour target and the CD3 protein on T cells. Tarlatamab, for example, is a DLL3 x CD3 bispecific T-cell engager used in small cell lung cancer.[1]

    Do T-cell engagers improve survival?

    In the phase 3 DeLLphi-304 trial, tarlatamab extended median overall survival to 13.6 months versus 8.3 months with chemotherapy in small cell lung cancer after platinum chemotherapy.[6]

    What is ivonescimab?

    A PD-1 x VEGF bispecific antibody. Its developer Akeso reported that it beat pembrolizumab on overall survival in PD-L1-positive lung cancer in HARMONi-2, and an FDA decision on a separate US application is due by 14 November 2026.[3][13]

    What side effects do T-cell engagers have?

    Labels for tarlatamab and teclistamab carry boxed warnings for cytokine release syndrome and neurologic toxicity, including ICANS.[11]

    Are T-cell engagers used in children?

    Yes. In a 2026 NEJM trial in 709 children with high-risk B-cell leukaemia, replacing two chemotherapy cycles with blinatumomab raised estimated 4-year event-free survival to 83.0% from 70.3%.[10]

    Sources

    Each numbered claim is a statement we checked against the sources listed with it. Status shows how well established it is.

    1. [1]

      On 16 May 2024 the FDA granted accelerated approval to tarlatamab (Imdelltra), a DLL3 x CD3 bispecific T-cell engager, for extensive-stage small cell lung cancer after platinum chemotherapy; 40% of 99 patients responded. confirmedas of 2024-05-16

    2. [2]

      On 5 March 2026 the FDA approved teclistamab, a BCMA x CD3 bispecific antibody, with daratumumab for relapsed or refractory myeloma after one prior line, based on the 587-patient MajesTEC-3 trial (progression-free survival hazard ratio 0.17). confirmedas of 2026-03-05

    3. [3]

      Akeso reported in September 2026 that its PD-1 x VEGF bispecific ivonescimab extended median overall survival to 30.8 months versus 22.6 months with pembrolizumab in first-line PD-L1-positive non-small cell lung cancer in the HARMONi-2 trial (hazard ratio 0.73). confirmedas of 2026-09-13

    4. [4]

      On 25 August 2026 the FDA approved zanidatamab, a HER2-targeted bispecific antibody, with the PD-1 inhibitor tislelizumab for first-line HER2-positive gastroesophageal adenocarcinoma; median overall survival was 26.4 versus 19.2 months (hazard ratio 0.72). confirmedas of 2026-08-25

    5. [5]

      On 2 June 2025 BioNTech and Bristol Myers Squibb agreed to co-develop the PD-L1 x VEGF-A bispecific BNT327, with $1.5 billion upfront, $2.0 billion in anniversary payments through 2028 and up to $7.6 billion in milestones. confirmedas of 2025-06-02

    6. [6]

      In the phase 3 DeLLphi-304 trial of 509 patients, tarlatamab extended median overall survival to 13.6 months versus 8.3 months with chemotherapy (hazard ratio 0.60), with fewer grade 3 or higher adverse events (54% vs 80%). confirmedas of 2025-07-24

    7. [7]

      In DeLLphi-304, adverse events led to treatment discontinuation in 5% of tarlatamab patients versus 12% with chemotherapy. confirmedas of 2025-07-24

    8. [8]

      In the phase 3 MajesTEC-3 trial (NEJM, December 2025), estimated 36-month progression-free survival was 83.4% with teclistamab-daratumumab versus 29.7% with standard daratumumab-based regimens; serious adverse events occurred in 70.7% versus 62.4%, and death from adverse events in 7.1% versus 5.9%. confirmedas of 2025-12-09

    9. [9]

      On 18 November 2025 the FDA approved epcoritamab-bysp for follicular lymphoma indications. confirmedas of 2025-11-18

    10. [10]

      In a 2026 NEJM trial of 709 children with newly diagnosed high-risk B-cell acute lymphoblastic leukaemia, replacing two chemotherapy cycles with the CD19 x CD3 T-cell engager blinatumomab gave estimated 4-year event-free survival of 83.0% versus 70.3% at a planned interim analysis (hazard ratio 0.51), with fewer treatment-related infections (23.9% vs 69.4%) but more neurotoxic events (12.0% vs 3.2%). confirmedas of 2026-09-01

    11. [11]

      T-cell engager labels such as tarlatamab's and teclistamab's carry boxed warnings for cytokine release syndrome and neurologic toxicity including ICANS. confirmedas of 2026-03-05

    12. [12]

      Akeso reported that in the 532-patient phase 3 HARMONi-6 trial in squamous non-small cell lung cancer, ivonescimab plus chemotherapy reduced the risk of death by 34% versus tislelizumab plus chemotherapy (hazard ratio 0.66); results were presented at the ASCO 2026 plenary. confirmedas of 2026-05-31

    13. [13]

      The FDA accepted Summit Therapeutics' application for ivonescimab plus chemotherapy in EGFR-mutated non-squamous non-small cell lung cancer after TKI therapy, with a decision goal date of 14 November 2026. confirmedas of 2026-01-29

    Revision history (2)
    1. Page created.
    2. Refresh: added MajesTEC-3 peer-reviewed detail, DeLLphi-304 discontinuation data and the 2026 NEJM paediatric blinatumomab trial.

    Created Oct 10, 2026. Last reviewed by an editor on Oct 10, 2026. Next scheduled review: Jan 10, 2027.

    Cite this page

    "Bispecific antibodies and T-cell engagers." ContentLora, updated Oct 10, 2026. https://contentlora.com/wiki/bispecific-t-cell-engagers

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