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The PD-1- and LAG-3-targeting bispecific molecule tebotelimab in solid tumors and hematologic cancers: a phase 1
Jason J Luke1, Manish R Patel2, George R Blumenschein3
1UPMC Hillman Cancer Center and University of Pittsburgh, Pittsburgh, PA, USA. lukejj@upmc.edu.
Abstract:
Tebotelimab, a bispecific PD-1×LAG-3 DART molecule that blocks both PD-1 and LAG-3, was investigated for clinical safety and activity in a phase 1 dose-escalation and cohort-expansion clinical trial in patients with solid tumors or hematologic malignancies and disease progression on previous treatment. Primary endpoints were safety and maximum tolerated dose of tebotelimab when administered as a single agent (n = 269) or in combination with the anti-HER2 antibody margetuximab (n = 84). Secondary endpoints included anti-tumor activity. In patients with advanced cancer treated with tebotelimab monotherapy, 68% (184/269) experienced treatment-related adverse events (TRAEs; 22% were grade ≥3). No maximum tolerated dose was defined; the recommended phase 2 dose (RP2D) was 600 mg once every 2 weeks. There were tumor decreases in 34% (59/172) of response-evaluable patients in the dose-escalation cohorts, with objective responses in multiple solid tumor types, including PD-1-refractory disease, and in LAG-3+ non-Hodgkin lymphomas, including CAR-T refractory disease. To enhance potential anti-tumor responses, we tested margetuximab plus tebotelimab. In patients with HER2+ tumors treated with tebotelimab plus margetuximab, 74% (62/84) had TRAEs (17% were grade ≥3). The RP2D was 600 mg once every 3 weeks. The confirmed objective response rate in these patients was 19% (14/72), including responses in patients typically not responsive to anti-HER2/anti-PD-1 combination therapy. ClinicalTrials.gov identifier: NCT03219268 .
Insights
Tebotelimab, a novel bispecific antibody, showed promising anti-tumor activity in advanced cancers, including PD-1 or CAR-T refractory disease. The recommended phase 2 dose was established for both monotherapy and combination treatments.
Area of Science:
- Immunotherapy
- Oncology
- Clinical Trials
Background:
- Immune checkpoint inhibitors targeting PD-1 and LAG-3 are crucial in cancer therapy.
- Tebotelimab is a bispecific DART molecule designed to block both PD-1 and LAG-3 pathways.
- Investigating novel immunotherapies is essential for patients with refractory malignancies.
Purpose of the Study:
- To evaluate the clinical safety and activity of tebotelimab in patients with advanced solid tumors or hematologic malignancies.
- To determine the recommended phase 2 dose (RP2D) for tebotelimab as monotherapy and in combination with margetuximab.
- To assess the anti-tumor response of tebotelimab, both alone and combined with margetuximab, in specific patient populations.
Main Methods:
- Phase 1 dose-escalation and cohort-expansion clinical trial (NCT03219268).
- Tebotelimab administered as monotherapy (n=269) or combined with margetuximab (n=84).
- Primary endpoints: safety and maximum tolerated dose; secondary endpoints: anti-tumor activity.
Main Results:
- Tebotelimab monotherapy: 68% treatment-related adverse events (TRAEs), RP2D 600 mg Q2W; 34% tumor decrease in evaluable patients, including PD-1 refractory and LAG-3+ lymphoma.
- Tebotelimab + margetuximab: 74% TRAEs, RP2D 600 mg Q3W; 19% objective response rate in HER2+ tumors, including non-responders to prior therapies.
- Demonstrated activity across multiple solid tumors and specific hematologic malignancies, even in refractory settings.
Conclusions:
- Tebotelimab is a clinically safe bispecific antibody with demonstrated anti-tumor activity in advanced cancers.
- The combination of tebotelimab with margetuximab shows potential in HER2+ tumors, including those resistant to standard treatments.
- Further investigation in phase 2 trials is warranted to confirm efficacy in diverse patient populations.
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