Science explainer

Why a trispecific T-cell engager for small cell lung cancer

Small cell lung cancer is where T-cell engagers were first proven in a solid tumor, and where more than 30 programs now crowd a single target. SBT-121 is a trispecific T-cell engager that engages 2 tumor antigens in 1 molecule, built for the patients who relapse after DLL3-directed therapy.

The disease

Small cell lung cancer (SCLC) accounted for about 268,000 new cases worldwide in 2022, out of 2.48 million lung cancers [1]. Roughly two thirds of patients present with extensive-stage disease [2], where median overall survival on first-line chemo-immunotherapy is 12 to 13 months [3, 4]. The tumor responds to first-line treatment and then relapses quickly, and many patients never get a second chance: in a 2025 US real-world series, just over 1 in 5 patients received both a first and a second line of therapy [5]. Durable treatment after relapse has been the unmet need for decades.

What tarlatamab proved

Tarlatamab, a DLL3 x CD3 T-cell engager, was the first TCE to show a survival benefit in SCLC: in the DeLLphi-304 trial, median overall survival was 13.6 months against 8.3 months on chemotherapy in relapsed disease [6]. It is now the preferred second-line option in US guidelines [7]. As first-line maintenance with durvalumab in DeLLphi-305, it extended median overall survival to 21.1 months against 12.7 months (hazard ratio 0.42) [8]. The target class is validated: a T-cell engager can control this tumor.

Where the field is stuck

More than 30 programs now target DLL3, with Amgen, Boehringer Ingelheim and Zelgen already in Phase 3 [9]. Two problems remain unanswered. Tumor heterogeneity means that not every tumor cell carries the same antigen at the same level, and antigen escape means that cells with low or lost expression survive treatment and drive relapse [2]. Differentiating on DLL3 alone is increasingly hard to show.

Why 2 tumor antigens in 1 molecule

A trispecific T-cell engager carries two tumor-binding arms and one CD3 arm. Engaging 2 tumor antigens means that T-cell engagement does not depend on a single antigen being present at a high level on every cell, which is the gap that relapse after DLL3-directed therapy exposes. SBT-121 is built for that setting, as a next treatment for patients whose disease has progressed on or after a DLL3-directed T-cell engager. The 2 antigens are disclosed under a confidentiality agreement.

Why a T-cell engager rather than an antibody-drug conjugate

Where the two modalities have been compared on the same target and line of therapy, T-cell engagers have produced deeper and more durable responses. In multiple myeloma (BCMA), TCEs reached response rates of 61 to 71% with a duration of response of 24 to 29 months [10, 11, 12], against 32% and about 12 months for the ADC [13]. In third-line and later diffuse large B-cell lymphoma, TCE duration of response was 18 to 21 months [14, 15] against 12 to 13 months for ADCs [16]. TCE responses also persist after fixed-duration dosing ends [14], which an ADC cannot offer.

How the molecule is chosen

A trispecific has more design variables than a bispecific: two binders, two epitopes, a CD3 arm and a format geometry that has to let all three engage at once. Rather than testing a few hundred combinations in plates, SBT-121 leads are screened functionally on TCELERATOR™, where thousands of designs are paired with tumor cells and reporter T cells in droplets and selected on T-cell activation and killing. Candidate binders are screened for off-target cross-reactivity with SERIS™ before they advance. Lead selection is under way, with a development candidate planned for mid-2027 and an IND in 2028 [17]. See the pipeline for the program overview.

References

1. Luo G, Zhang Y, Rumgay H, et al. Estimated worldwide variation and trends in incidence of lung cancer by histological subtype in 2022 and over time. Lancet Respir Med 2025. doi:10.1016/S2213-2600(24)00428-4

2. Rudin CM, Brambilla E, Faivre-Finn C, Sage J. Small-cell lung cancer. Nat Rev Dis Primers 2021;7:3.

3. Horn L, et al. First-line atezolizumab plus chemotherapy in extensive-stage small-cell lung cancer (IMpower133). N Engl J Med 2018;379:2220.

4. Paz-Ares L, et al. Durvalumab plus platinum-etoposide in extensive-stage small-cell lung cancer (CASPIAN). Lancet 2019;394:1929.

5. Halmos B, Anand S, Juneau P, et al. Real-world treatment patterns in ES-SCLC highlight continued unmet medical need in the era of new therapies (ESSENCE). World Conference on Lung Cancer 2025.

6. Mountzios G, et al. Tarlatamab in small-cell lung cancer after platinum-based chemotherapy (DeLLphi-304). N Engl J Med 2025.

7. NCCN Clinical Practice Guidelines in Oncology, Small Cell Lung Cancer.

8. Pérol M, et al. Tarlatamab plus durvalumab as first-line maintenance in extensive-stage small-cell lung cancer (DeLLphi-305). N Engl J Med 2026.

9. ShennonBio competitive landscape analysis, Aug 2026, from ClinicalTrials.gov and company disclosures.

10. Moreau P, et al. Teclistamab in relapsed or refractory multiple myeloma (MajesTEC-1). N Engl J Med 2022;387:495.

11. Lesokhin AM, et al. Elranatamab in relapsed or refractory multiple myeloma (MagnetisMM-3). Nat Med 2023;29:2259.

12. Bumma N, et al. Linvoseltamab for treatment of relapsed/refractory multiple myeloma (LINKER-MM1). J Clin Oncol 2024;42:2702.

13. Lonial S, et al. Belantamab mafodotin for relapsed or refractory multiple myeloma (DREAMM-2). Lancet Oncol 2020;21:207.

14. Dickinson MJ, et al. Glofitamab for relapsed or refractory diffuse large B-cell lymphoma. N Engl J Med 2022;387:2220.

15. Thieblemont C, et al. Epcoritamab in relapsed or refractory large B-cell lymphoma (EPCORE NHL-1). J Clin Oncol 2023;41:2238.

16. Caimi PF, et al. Loncastuximab tesirine in relapsed or refractory diffuse large B-cell lymphoma (LOTIS-2). Lancet Oncol 2021;22:790.

17. ShennonBio non-confidential corporate presentation, Nov 2026.

Built for relapse after DLL3-directed therapy