The New Frontier in SCLC Treatment: 4 Antigens Driving Antibody Innovation

Small cell lung cancer (SCLC) remains one of the most aggressive and lethal forms of lung cancer with limited treatment options and poor prognosis, accounting for 15% of current lung cancer patient population (Figure 1). In recent years, advances in antibody-based drug development have opened new avenues for targeted therapy in SCLC. Among these, delta-like ligand 3 (DLL3), seizure-related 6 homolog-like (SEZ6L), B7 homolog 3 (B7-H3), and trophoblast cell surface antigen 2 (TROP2) have emerged as promising surface antigens due to their high expression in SCLC and limited expression in normal tissues. This review summarizes the current research and clinical landscape of antibody therapeutics targeting these four molecules, discussing their mechanisms of action, trial progress, and potential challenges.

Figure 1. Classifications of lung cancer [1]. Picture Resources: Lung Cancer Foundation of America. 

Target Overview

DLL3 (Delta-like ligand 3) is a member of the Notch ligand family, functioning as an atypical ligand that negatively regulates the Notch signaling pathway. DLL3 is primarily localized in the Golgi apparatus and inhibits the pathway in a cell-autonomous manner during embryonic development. In cancer, particularly SCLC, DLL3 is highly and selectively expressed on the surface of tumor cells while being largely absent from normal adult tissues. This restricted expression profile makes DLL3 an attractive target for therapeutic development. It has been explored in clinical trials using various modalities, including antibody-drug conjugates (ADC), bispecific T-cell engagers (TCE), and CAR-T cell therapies2,3.

SEZ6 (Seizure-related 6 homolog) is a type I transmembrane protein implicated in neuronal development, synapse formation, and possibly in proteolytic signaling pathways, although its precise biological functions remain incompletely defined. Originally studied in the context of the central nervous system, SEZ6 has recently gained attention in oncology due to its upregulation in neuroendocrine tumors, particularly SCLC. It shows limited expression in normal adult tissues, which contributes to its appeal as a potential tumor-specific antigen. Preclinical studies have identified SEZ6 as a promising target for antibody-based therapies, including ADCs, which are now being explored in early-phase clinical development for SCLC4,5.

B7-H3 (CD276) belongs to the B7 family of immune checkpoint molecules and modulates T-cell responses. Although the exact receptor and signaling mechanisms of B7-H3 remain elusive, it is known to contribute to immune evasion and may also support tumor cell proliferation, invasion, and angiogenesis. B7-H3 is overexpressed in a wide range of solid tumors, including SCLC, while its expression in normal tissues is relatively limited. This differential expression, coupled with its role in immune suppression, has spurred the development of several B7-H3-targeted therapeutic strategies, including ADCs, bispecific antibodies, and CAR-T cell therapies, which are currently under clinical investigation6,7.

TROP2 (Trophoblast cell surface antigen 2), or TACSTD2, is a transmembrane glycoprotein involved in cell signaling, adhesion, and proliferation. It is frequently upregulated in a broad spectrum of epithelial cancers and is associated with increased tumor aggressiveness, metastasis, and poor clinical outcomes. In SCLC, TROP2 is often overexpressed and has emerged as a promising therapeutic target. The most notable TROP2-targeted therapy is sacituzumab govitecan, an FDA-approved antibody-drug conjugate that delivers the cytotoxic payload SN-38. While sacituzumab govitecan is approved for use in other epithelial tumors such as triple-negative breast cancer, its utility is currently being explored in SCLC through ongoing clinical trials8,9.

Clinical Trial Landscape

DLL3-targeting therapies have shown mixed results in clinical development. Rovalpituzumab-tesirine (Rova-T, or ABBV-321, AbbVie) initially generated interest but ultimately failed in Phase III trials due to significant toxicity10,11. Newer approaches include bispecific T-cell engagers such as HPN328 (Harpoon Therapeutics) and AMG 757 (Amgen), both of which target DLL3 and CD3. AMG 757 has shown early signs of clinical efficacy with manageable toxicity in ongoing trials  while HPN328 is currently being evaluated in Phase I/II studies12,13.

SEZ6-based therapies remain in the preclinical stage but are gaining momentum. Antibody-drug conjugates (ADCs) and chimeric antigen receptor T (CAR-T) cells targeting SEZ6 are undergoing laboratory development, with no clinical trials yet initiated14. However, the increasing interest in SEZ6 as a tumor-specific antigen suggests that investigational new drug (IND) applications may be filed in the near future.

B7-H3-directed therapies are more advanced in clinical testing. MGC018 (Macrogenics), a B7-H3-targeting ADC, is currently in a Phase I/II trial for SCLC and other indications. Enoblituzumab (Macrogenics), a monoclonal antibody against B7-H3, has been tested in several solid tumors and may be expanded to include SCLC15,16. Additionally, radioimmunoconjugates such as 131I-omburtamab (Y-mAb Therapeutics), initially developed for neuroblastoma, show potential for broader application, possibly including SCLC16.

TROP2-targeted agents are also under active investigation in SCLC. Sacituzumab govitecan (Gilead Sciences), an FDA-approved ADC for other epithelial cancers, is now being evaluated in SCLC patients in trials18. Another promising TROP2-directed ADC, datopotamab deruxtecan (Dato-DXd, Daiichi Sankyo/AstraZeneca), is in clinical trials and includes cohorts for SCLC among other tumor types, reflecting its broad therapeutic potential19.

Table 1. Current clinical trials of DLL3, B7-H3 and TROP2 for SCLC indication.

Challenges, Opportunities, and Future Directions

While antibody-based therapies show promise SCLC treatments, several challenges hinder their efficacy. Tumor heterogeneity, low antigen density, and off-tumor expression—particularly with SEZ6 and B7-H3—can limit therapeutic impact and raise safety concerns. Risks are also in ADCs such as neutropenia and liver toxicity, and the immunosuppressive tumor microenvironment may dampen the effectiveness of immune-cell engagers.

Despite these hurdles, opportunities lie in rational combination therapies (e.g., ADCs with immune checkpoint inhibitors), improved payload design, and next-generation bispecifics. Future efforts should focus on biomarker-driven patient selection, novel formats like masked antibodies and conditionally activated ADCs, and deeper exploration of underdeveloped targets such as SEZ6. Continued investment in DLL3 and TROP2 ADCs, particularly in relapsed SCLC, is expected.

KACTUS Solutions for SCLC research

KACTUS is proud to support antibody drug research and development by providing high-quality TROP2, DLL3, SEZ6, and B7-H3 recombinant proteins. With a commitment to scientific excellence and product consistency, KACTUS aims to accelerate the discovery and optimization of next-generation therapeutics for SCLC as well as other indications:

Product Validation Data

Immobilized Human DLL3, His Tag at 0.1 ug/mL (100 ul/well). Dose response curve for Anti-DLL3 Antibody, hFc Tag with the EC50 of 2.6 ng/ml determined by ELISA

Immobilized Human SEZ6, His Tag at 1 ug/ml (100 ul/well) on the plate. Dose response curve for Anti-SEZ6 Antibody, hFc Tag with the EC50 of 9.0 ng/ml determined by ELISA 

Immobilized Human B7-H3, His Tag at 1 ug/ml (100 ul/Well) on the plate. Dose response curve for Anti-B7-H3 Antibody, hFc Tag with the EC50 of 9.9 ng/ml determined by ELISA

Immobilized Human TROP-2, His Tag at 0.5 ug/ml (100 ul/Well). Dose response curve for Anti-TROP-2 Antibody, hFc Tag with the EC50 of 2.2 ng/ml determined by ELISA 

Ordering Information

References

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