Seizure-Related Homolog Protein 6 (SEZ6): Biology and Therapeutic Target in Neuroendocrine Carcinomas

Abstract

Seizure-related homolog protein 6 (SEZ6) is a cell surface type 1 transmembrane protein involved in neuronal development, expression of which in adult tissues is almost exclusively limited to the central nervous system. Aberrant expression of SEZ6 has been associated with neurodevelopmental and psychiatric disorders including epilepsy, schizophrenia, and Alzheimer’s disease. More recently, SEZ6 overexpression has been detected in small cell lung cancer (SCLC) and other high-grade neuroendocrine malignancies, although our understanding of the function of SEZ6 as a driver of cancer is limited. A lineage-defining transcription factor of SCLC, ASCL1, has been implicated as a regulator of SEZ6 expression. SEZ6 has emerged as a novel target for antibody-drug conjugate (ADC) therapy, and early studies have shown promising antitumor activity, demonstrating the potential for SEZ6 to be targeted by drugs with alternate mechanisms of action. Here, we review the current knowledge of the biology of SEZ6 and its implications in malignancy, summarize the preclinical and clinical findings of SEZ6 targeted ADCs, and discuss future directions to further elucidate the role of SEZ6 in SCLC and other neuroendocrine neoplasms.

Introduction

Neuroendocrine neoplasms (NEN) represent a diverse group of cancer types that can arise in various organs, mainly the gastrointestinal tract and the lungs, and share common neuroendocrine (NE) features. NENs can be broadly divided into well-differentiated and typically indolent neuroendocrine tumors (NET) and poorly differentiated, high-grade neuroendocrine carcinomas (NEC), the latter of which are characterized by rapid proliferation, high metastatic potential and an exceptionally poor prognosis (1). This review will mainly focus on NECs, among which small-cell lung cancer (SCLC) is the most common and extensively studied. In SCLC and other NECs, there is a great unmet need for more effective therapies.

First line treatment of NECs usually includes a platinum agent in combination with a topoisomerase inhibitor. Immune checkpoint inhibition (ICI) with programmed death 1/programmed death ligand 1 (PD1/PD-L1) inhibitors has largely revolutionized modern oncology, and the addition of ICI to chemotherapy is considered a standard of care for patients with extensive stage SCLC (2, 3). Despite high initial response rates, most patients will relapse and develop treatment-resistant disease with limited therapeutic options (4). Durable benefit from the addition of ICI is limited to a small minority of patients with SCLC, and for other NECs the effects of ICI are not yet established. Hence, the development of other treatment strategies is imperative.

Seizure-related homolog protein 6 (SEZ6) is currently under investigation as a novel target in neuroendocrine malignancies based on bioinformatic analyses that have nominated this as a tumor-selective target (5). SEZ6 is a transmembrane protein primarily expressed by neuronal cells (6), with very limited detection in normal tissues outside the central nervous system. In malignancy, SEZ6 appears to be selectively expressed by high-grade neuroendocrine cancer cells, making it suitable as a therapeutic target (5). Data from preclinical and early clinical studies have shown robust anti-tumor activity with SEZ6-targeting ADCs. However, much remains unknown regarding the role of SEZ6 in neuroendocrine malignancy. To our knowledge, this is the first review to systematically examine the role of SEZ6 in normal biology, in oncogenesis, and as a rational therapeutic target.

I. SEZ6 - normal biology

i. Protein structure and regulatory pathways

SEZ6 was originally described in 1995 as a brain-specific protein induced by the convulsant drug pentylenetetrazol (7). SEZ6 is an N-glycosylated transmembrane protein composed of five short consensus repeat (SCR) domains and three CUB domains (named after complement C1r/C1s, Uegf, Bmp1), with a short, cytoplasmic domain (Fig. 1a) (7, 8). The SEZ6 protein family includes two structurally similar members, SEZ6L and SEZ6L2. The three SEZ6 family proteins are encoded by genes located on different chromosomes; Chr 17, 22 and 16, for the genes SEZ6, SEZ6L and SEZ6L2, respectively (9). The SEZ6 gene appears to be highly polymorphic, with multiple single-nucleotide variants reported (10). Most of these are considered variants of unknown significance, having not been definitively linked to disease states, though some have been associated with neurological disorders as discussed below (11–13).

Figure 1: SEZ6 protein structure and SEZ6 expression in normal tissues.

A. SEZ6 is a type 1 transmembrane protein consisting of repeated motifs of short consensus repeats and CUB domains. The full-length protein is composed of a 994 amino acid sequence. (Created with BioRender. Gezelius, E. [2025] https://BioRender.com/fai88lr.) B. Relative SEZ6 expression across normal human tissues is shown. Expression is primarily limited to central nervous system (CNS; yellow) tissues and pituitary (purple), with low level detectable expression in gastrointestinal (GI; blue) tissues including colon, stomach, pancreas, and small intestine, with similar low-level expression in testis. Data from Consensus data set of The Human Protein Atlas (https://www.proteinatlas.org).

SEZ6 = Seizure-related homolog protein 6; CUB = complement C1r/C1s, Uegf, Bmp1; SCR = short consensus repeat.

The regulatory pathways of SEZ6 have not been fully elucidated, although there is evidence suggesting that SEZ6 may be upregulated by ASCL1, a key lineage-determining transcription factor in neuroendocrine malignancies. Kudoh et al. (14) found strong upregulation of SEZ6 in ASCL1-positive, as compared to ASCL1-negative, SCLC cell lines, and demonstrated that ASCL1-transfection induced SEZ6 in otherwise ASCL1-negative non-small cell lung cancer (NSCLC) cells. Furthermore, SEZ6 expression was detected by immunohistochemistry (IHC) in xenotransplants of ASCL1-positive, but not ASCL1-negative, NSCLC tumors. The mechanisms controlling gene expression have not been defined, and functional studies are needed to establish whether ASCL1 binds directly to the SEZ6 gene locus or if an intermediate step is required. Still, the data provides a potential connection between SEZ6 and neuroendocrine malignancies. In addition, SEZ6 might be upregulated by neuronal activity, as illustrated by its induction by convulsant drugs (7, 15). Downstream signaling pathways have not yet been described.

ii. SEZ6 function in normal development and disease

SEZ6 is primarily expressed by neuronal cells, with particularly high levels in the developing forebrain during embryonic and neonatal stages (16). The expression gradually decreases after birth, and in the adult brain SEZ6 is predominantly located in layers V and VI of the cerebral cortex, the CA1 region of the hippocampus, the striatum and olfactory tubule, with weak or absent expression in most other areas (6, 16–18). The evolving expression patterns during embryonic and postnatal stages reflect its role in neural development, as SEZ6 is an important regulator of dendritic arborization and synaptic connectivity (19, 20). Animal models of SEZ6-null mice are viable, fertile and in many respects similar to their wildtype counterparts. However, they exhibit impaired motor function and behavioral changes, and global knock-out of all SEZ6 family members further affects behavioral and cognitive function (17, 19). These aspects should be taken into consideration when assessing the potential side-effects of SEZ6 targeting therapies. In tissues outside the central nervous system, SEZ6 detection is minimal, with low expression levels in the pituitary, testis, and the highly innervated gastrointestinal tract (Fig. 1b) (5, 6).

Both SCR and CUB domains, which are constituents of SEZ6, have been shown to be involved in protein-protein interactions including cell adhesion and recognition, and regulation of the complement cascade which plays a fundamental role in the innate immune system (21, 22). Qiu et al. (23) demonstrated that SEZ6 inhibits the complement cascade and restricts C3b opsonization by the classical and alternative pathways. SEZ6 has also been shown to interact with motopsin, a protease secreted by neurons, essential for maintaining cognitive function (24). Whether SEZ6 is involved in cell adhesion and protein-protein interactions outside neural tissue remains to be established, and its role in cancer cells in particular has not been defined.

Numerous studies implicate SEZ6 in neuropsychiatric disorders. Genetic variants (the function of which, gain versus loss of function, are unclear in the literature) have been found at increased frequency in patients with febrile seizures and epilepsy, nominating SEZ6 as a seizure-susceptibility gene (12, 13, 25), as alluded to by its name. An enrichment in single nucleotide variants has also been noted in childhood onset schizophrenia, Alzheimer’s disease and autosomal recessive non-syndromic hearing impairment (11, 26, 27). In addition, chronic pain and psychiatric illness has been associated with increased SEZ6 levels in the cerebrospinal fluid (28, 29). Whether these findings are causative or secondary effects has not been determined. In neurons, both SEZ6 and SEZ6L can be cleaved by BACE1, a β-site APP cleaving enzyme, generating the soluble forms sSEZ6 and sSEZ6L which are shed into the cerebrospinal fluid (30). This may have clinical implications as BACE1 contributes to β-amyloid plaque deposition and aggregation of neurofibrillary tangles, key features of Alzheimer’s disease (31). Interestingly, several pharmaceutical BACE1 inhibitors have been explored in Alzheimer’s disease, however, to date, all agents have been discontinued due to futility or toxicity concerns (32). Still, SEZ6 may serve as a future biomarker for disease monitoring in Alzheimer’s disease. The key advances relating to SEZ6 biology and therapeutic development are depicted in Figure 2.

Figure 2. Timeline of key developments relating to SEZ6 biology and therapeutic advances.

Pivotal findings concerning normal expression and function (below the timeline), association to neuroendocrine malignancy (above the timeline; light purple) and development of SEZ6-targeted therapy (above the timeline; dark purple).

SCLC = small-cell lung cancer; NE = neuroendocrine; Top1 = topoisomerase 1; ADC = antibody-drug conjugate; SEZ6 = Seizure-related homolog 6; BACE1 = β-site APP cleaving enzyme.

II. SEZ6 in oncogenesis and neuroendocrine differentiation

SCLC has recently been classified into molecular subtypes based on differential expression of the transcription factors ASCL1, NEUROD1 and POU2F3, defining the subtypes SCLC-A, SCLC-N and SCLC-P, respectively (33, 34). The fourth subtype with low-level expression of all three of these transcription factors has been variably described as expressing YAP1, and in some cases is enriched for markers of inflammation (35, 36). SCLC-A and SCLC-N account for ~80% of all SCLC tumors, and display a NE-high signature, encompassing the expression of typical NE-markers such as chromogranin A, synaptophysin, INSM1 and CD56 (33, 34). Other SCLC subtypes generally manifest lower expression of neuroendocrine markers (35, 37). The subtypes do not yet inform routine clinical decision-making, although data are suggestive of differential therapeutic vulnerabilities. With respect to therapeutic agents targeting NE-related markers, it may be reasonable to assume a preferential response in NE-high subtypes, although this remains to be demonstrated clinically. The NE transcription factors have been explored in other NECs as well, including prostate (38–40), gastroenteropancreatic (41, 42) and pulmonary large cell NEC (LCNEC) (43). Further research is called for to define the value of transcriptional subtypes in these, and other, high-grade NECs.

Several reports support a link between SEZ6 and neuroendocrine malignancy. In addition to its proposed regulation by ASCL1 (14), SEZ6 has also been reported to be significantly upregulated in platinum-resistant SCLC cell lines, although clinical data to confirm an association with therapy resistance is lacking (44). Overall, the role of SEZ6 in malignancy is not yet understood, and preclinical studies directed at elucidating the function of SEZ6 are warranted. Based on our current understanding, it is plausible that SEZ6 is not oncogenic per se, but rather a marker of NE differentiation.

i. Overexpression in SCLC and other neuroendocrine neoplasms

In pursuit of a candidate ADC target in SCLC, Wiedemeyer et al. (5) performed a genome-wide bioinformatic survey focusing on markers associated with chromogranin A. Chromogranin A is an established marker of NE differentiation (45), but it is a protein that sorts into secretory granules and, thus, lacks properties of a suitable therapeutic target. Upon querying multiple tumor models, SEZ6 was found to be uniquely expressed in SCLC and other neuroendocrine carcinomas, including LCNEC (5). Furthermore, SEZ6 expression was considerably higher in tumors with NE-high profiles, as defined by their predominant expression of ASCL1 or NEUROD1, which is in line with previous data identifying SEZ6 as one of the top 25 genes most strongly correlated to NE differentiation in SCLC (46).

A prognostic value of SEZ6 has been suggested, as RNA expression levels above the median were associated with reduced survival compared to levels below the median, in an analysis of three merged SCLC cohorts (N=188; P-value=0.027) (5). However, a recent report including 112 SCLC patients from a real-world cohort did not confirm SEZ6 as a prognostic marker (47). Similarly, in medullary thyroid cancer, another neuroendocrine neoplasm in which upregulated expression of SEZ6 has been detected, expression level did not correlate with prognosis (48). Given the heterogeneity of study populations in these early datasets, including underlying disease of interest, and lack of clarity of a putative mechanism for SEZ6 to impact clinical outcomes, it is clear that prospective studies of the role of SEZ6 as a prognostic factor will be of great importance.

ii. SEZ6L and SEZ6L2 in malignancy

Although SEZ6L and SEZ6L2 bear structural and functional resemblance to SEZ6, with shared anatomical distribution within the CNS (17, 23, 30, 49), there are currently no data supporting an association between SEZ6L or SEZ6L2 and high-grade NECs. In the exploratory bioinformatics surveys mentioned above (5, 46), neither SEZ6L nor SEZ6L2 emerged as strong NE-related markers. Nonetheless, there is some evidence suggesting a connection between non-neuroendocrine cancer and the two SEZ6 family members. A SEZ6L polymorphism has been proposed as a risk allele for lung cancer (50, 51) and serum-based detection of SEZ6L was included in a multiprotein classifier for early detection of ovarian cancer (52). SEZ6L hypermethylation has been identified in colorectal cancer (53) and, in pancreatic cancer, SEZ6L expression might correlate with a favorable prognosis (54). As for SEZ6L2, increased expression has been associated with reduced survival in various malignancies, including cholangiocarcinoma, hepatocellular carcinoma and non-small cell lung cancer (55–57). Additionally, an upregulation of SEZ6L2 has been found in drug resistant lung adenocarcinoma cells and in tumor spheroid cells (58), suggesting an involvement in oncogenic processes. Most of these putative associations have not been confirmed. To further interrogate the functions of SEZ6L and SEZ6L2 in neuroendocrine neoplasms, and the possible implications for therapies targeting the SEZ6 family, pre-clinical studies and deep molecular profiling are needed.

III. SEZ6 detection

i. Immunohistochemistry

Immunohistochemical (IHC) staining for SEZ6 is not yet implemented into routine practice, but several antibodies are commercially available, of which two primary antibody clones have recently been evaluated in medullary thyroid cancer (48). The results were comparable, with 91% SEZ6 positivity using the SC17.14 clone and 93% positivity using the 14E5 clone, based on H-scores ≥125 and ≥100, respectively, as thresholds for positivity. The sensitivity and specificity of SEZ6 were 91% (95% CI = 84%−99%) and 96% (95% CI = 90%−101%) respectively for the SC17.14 clone, and 93% (95% CI = 86%−100%) and 96% (95% CI = 90%−101%) respectively for the 14E5 clone. SEZ6 is frequently expressed in SCLC tumors (Fig. 3a), as demonstrated by Morgensztern at al. (59), detecting any SEZ6 positivity in 86% of 445 evaluable SCLC tissue samples, with 55% meeting a pre-specified cutoff of ≥25% positive tumor cells with ≥1+ intensity. Similarly, IHC evaluation of 73 SCLC tumor samples revealed that 78% of the cases expressed SEZ6 in ≥5% of cells, with a median H-score of 55 (5). While SEZ6 protein expression across NE cancers is still being defined, some data are beginning to emerge. For example, high median H-scores of 180, 127 and 108 were recently reported in high-grade NET, neuroendocrine prostate cancer and transformed SCLC, respectively (Fig. 3b) (60), however, the findings need to be confirmed in larger cohorts.

Figure 3: SEZ6 expression by immunohistochemistry in neuroendocrine carcinomas.

A. SEZ6 expression in small cell lung carcinoma, using a mouse monoclonal antibody (clone SC17.14) demonstrating strong SEZ6 expression. B. Immunohistochemical evaluation of SEZ6 expression showing high median H-scores in several neuroendocrine neoplasms (60).

H&E = hematoxylin and eosin; NET = neuroendocrine tumor; NEPC = neuroendocrine prostate cancer; T-SCLC = transformed small cell lung cancer; MTC = medullary thyroid cancer; LCNEC = large cell neuroendocrine carcinoma; GEP-NEC = gastroenteropancreatic neuroendocrine carcinoma.

ii. Molecular profiling

With regard to molecular profiling of SEZ6, data from publicly available datasets include missense mutations in 2% of SCLC (61, 62). The significance of this observation is unknown, and the variants may not be deleterious. To our knowledge, there is no genomic SEZ6 alteration with oncogenic properties.

IV. SEZ6 targeting therapy

i. ABBV-011

ABBV-011, the first SEZ6-targeting ADC to be developed, consists of the anti-SEZ6 monoclonal antibody SC17 linked to a calicheamicin-based payload (5). Calicheamicin is a natural toxin derived from the Micromonospora echinospora bacteria, naturally found in soil and lake sediments (63, 64). In recognition of its DNA-damaging properties, calicheamicin is already a component of two FDA-approved ADCs marketed for the treatment of hematological malignancies; gemtuzumab ozogamicin, targeting CD33, and inotuzumab ozogamicin, targeting CD22. These prior agents have employed an acid labile linker drug, dimethylhydrazine (DMH), which generates circulating toxic metabolites, limiting their use. To overcome the toxicity related to the DMH metabolites, ABBV-011 was designed with a non-cleavable linker drug, LD19.10 (Fig. 4a). In vitro experiments have shown that ABBV-011 induces target-specific cell killing in SCLC cell lines (5). These findings were confirmed in vivo, where tumor regression was demonstrated in PDX-models with high (80–99% positive cells) or intermediate (60% positive cells) SEZ6 expression by IHC. In models with minimal SEZ6 expression (2% positive cells), no tumor-inhibiting effects were seen, indicating a target-dependent activity. In sensitive models, ABBV-011 induced more robust responses than a single dose of cisplatin-etoposide.

Figure 4: Structure of antibody-drug conjugates targeting SEZ6.

Both agents are composed of the monoclonal antibody SC17. A. ABBV-011 employs a non-cleavable linker and calicheamicin payload with a DAR of 2; B. ABBV-706 uses a cathepsin cleavable linker and a topoisomerase 1 inhibitor at a DAR of 6. (Created with BioRender. Gezelius, E. [2025] https://BioRender.com/fai88lr.)

DAR = drug-to-antibody ratio.

Initial clinical activity was reported in the recently published phase-I trial of ABBV-011 that included patients with relapsed or refractory SCLC, previously treated with ≥1 platinum-based chemotherapy regimen (NCT03639194) (59). A total of 99 patients were enrolled of which 40 were part of a dose-expansion cohort receiving the recommended dose of 1 mg/kg. This dose was initially set to 2 mg/kg, but delayed hepatotoxicity reinforced the need for a dose reduction. For the dose-escalation phase there were no requirements for SEZ6 expression, whereas patients in the dose-expansion cohort were preselected based on SEZ6 positivity, defined by IHC expression in ≥25% of cells with ≥1% intensity. In the overall population (N=98), objective response rate (ORR) and clinical benefit rate (CBR) were 19% and 69%, respectively, with clinical benefit maintained for at least 12 weeks in 37% (59). Response rates were comparable in the dose-expansion cohort, with ORR of 25% and CBR of 65%. Efficacy was noted in patients with ≥2 prior treatment lines, or with treatment-free interval <90 days, factors which are otherwise considered to predict poor response to subsequent therapy. The most frequently observed treatment-emergent adverse events were fatigue (50%), nausea (42%), thrombocytopenia (41%) and decreased appetite (40%). In the overall population, hepatotoxicity was reported in 42% at all grades, with increased levels of aspartate aminotransferase (22%), gamma-glutamyl transferase (21%) and bilirubin (18%) being the most common indicators. Grade ≥3 hepatotoxicity was observed in 12% and 13% in the overall and dose-expansion cohorts, respectively. Of note, two patients developed grade 3 veno-occlusive disease, which resolved with supportive measures. No adverse effects on neurological or cognitive function were described. Altogether, the findings were considered promising, although the hepatotoxicity warrants attention for appropriate dose finding. Further results from the phase I trial are pending, including outcome from the third study arm on which ABBV-011 was given in conjunction with the PD-1 inhibitor budigalimab, as well as translational data and correlative analyses of SEZ6 expression.

ii. ABBV-706

To mitigate the toxicity concerns associated with the calicheamicin payload, a second SEZ6-targeting ADC has been developed. ABBV-706 is composed of the same monoclonal antibody but employs a topoisomerase I inhibitor as the cytotoxic payload (Fig. 4b) (65). Topoisomerase I inhibitors are well-established chemotherapy agents, used in several solid malignancies including SCLC, and make up the cytotoxic warhead in two FDA-approved ADCs; sacituzumab govitecan and trastuzumab deruxtecan (66).

Pre-clinical evidence indicated superior tumor-inhibiting effects with ABBV-706 compared to ABBV-011 in SCLC and other SEZ6-expressing neuroendocrine carcinoma models (65). In a first-in-human study (NCT05599984) enrolling SCLC (N=23), other neuroendocrine neoplasms (N=25) and high-grade CNS tumors (N=5), confirmed ORR was 43.8% and the CBR was 91.7% in the whole cohort (67). Subgroup analysis by cancer type showed ORR of 60.9% in SCLC and 28% in NEN. No responses were observed in the five patients with primary CNS tumors. Adverse events were mainly hematological, and included anemia (60%), neutropenia (49%) and thrombocytopenia (38%), as well as fatigue (66%). No neuro- or hepatotoxicity was reported in this early phase trial, for which the full report is awaited. The favorable profile of ABBV-706 has led to the discontinuation of ABBV-011 development. A detailed summary of available data from clinical trials is provided in Supplementary Table S1.

V. Anticipated side-effects

Due to the limited clinical experience of SEZ6-targeting ADCs, the range of adverse events may not yet be fully appreciated. With ABBV-011, liver toxicity was of particular concern, especially the development of veno-occlusive disease which occurred in 2% of the participants (59). This is considered a class effect of calicheamicin and, hence, is not expected with ABBV-706. Preliminary data from the first-in-human study of ABBV-706 suggested a manageable toxicity profile, predominantly hematological in nature (67).

Considering the high abundance of SEZ6 in the central nervous system, the risk of neurological toxicity could have been thought to pose a risk, but such signals have not yet been observed. However, conjugated antibodies are large molecules that were initially perceived to be restricted by the blood-brain barrier and, importantly, no neurological or ocular adverse events were reported in the two early clinical reports (59, 67). Interestingly, trastuzumab-deruxtecan, an ADC targeting human epidermal growth factor receptor 2 (HER2) which is approved in metastatic HER2-positive non-small cell lung cancer, yielded an intracranial response rate of 25% in patients harboring brain metastases (68). Similarly, a HER3-targeted ADC showed intracranial ORR of 20% in patients with CNS metastases, of which patients without prior brain irradiation displayed ORR of 33% (69). This suggests that ADCs have the capacity to cross the blood-brain barrier, at least in the context of metastatic disease. The potential intracranial efficacy of SEZ6-targeting agents will be of particular relevance in SCLC and LCNEC, where the risk of brain metastases is considerable (1, 70).

VI. Conclusions and future directions

While SEZ6 has been more extensively studied in the context of neurological development and disease, the role in malignancy is less well-defined and it remains unclear whether SEZ6 actively contributes to oncogenesis or is merely a marker of NE differentiation. Nonetheless, SEZ6 is emerging as an attractive therapeutic target for patients with SCLC and other high-grade NECs, where treatment options are scarce. The final report of the phase 1 ABBV-706 trial is pending, but initial reported efficacy and safety signals are promising. That SEZ6 has been reported to be upregulated in platinum-resistant SCLC is intriguing (44) and may provide a rationale for the use of SEZ6-targeted ADCs in platinum-resistant patients. The observation that ABBV-011 showed responses in patients with treatment-free interval < 90 days is also encouraging, as treatment-resistant patients represent a therapeutically challenging group. Looking beyond ADCs, these early results suggest that SEZ6 might serve as a therapeutic target in other novel modalities of delivering cancer treatment, such as T-cell engagers, chimeric antigen receptor T (CAR-T) cell therapies, and radiopharmaceuticals (Fig. 5).

Figure 5: Future directives.

Potential therapeutic approaches leveraging SEZ6 as a tumor-selective target in neuroendocrine malignancies. A. Upon binding the tumor-associated antigen, ADCs are internalized and undergo cleavage, with subsequent release of the cytotoxic payload leading to cell death. B. Bi-specific T cell engagers simultaneously bind the target antigen and CD3 on T cells. This leads to T cell expansion and activation, and the release of pore-forming enzymes such as perforin and granzymes, causing tumor cell apoptosis and an augmented T cell response. C. Radioimmunoconjugates consist of antibodies linked with a radionuclide emitting α- or β-particles, inducing cell death primarily through the generation of reactive oxygen species. D. CAR-T cells are genetically modified, autologous T cells that are engineered to express a specific receptor, targeting the tumor surface antigen. Binding to the target triggers the activation and expansion of CAR-T cells, resulting in the release of pore-forming enzymes and subsequent cell death. (Created with BioRender. Gezelius, E. [2025] https://BioRender.com/fai88lr.)

ADC = antibody-drug conjugate; CAR-T = chimeric antigen receptor T cell.

While it is clear that SEZ6-targeting therapies herald an exciting era of new options for patients with SCLC and other neuroendocrine neoplasms, their ongoing development in a rapidly shifting treatment landscape merits some discussion. The delta-like ligand 3 (DLL3)-targeting bispecific T-cell engager tarlatamab has cemented itself as a standard of care in the second-line setting for SCLC (71), and several ongoing trials are exploring the use of this agent in the first-line, maintenance, and earlier-stage settings (NCT05361395, NCT06211036, NCT06117774). Concurrently, other novel targeted agents for SCLC and other NENs such as ADCs targeting trophoblast cell surface antigen 2 (TROP2) and B7 homolog 3 (B7H3) (72–74) are also poised to offer additional treatment strategies and may very well further alter the accepted standard of care. While tarlatamab has been hailed as a revolutionary agent, unfortunately, its remarkable benefits do not ultimately translate to all patients (71). Compelling new data indicate higher expression levels of SEZ6 compared to DLL3, B7-H3 and TROP2 in SCLC, particularly in NE-high subtypes (75, 76). Future work is needed to more deeply understand the optimal treatment strategy and sequencing for each patient as the availability of multiple targeted agents expands.

In the era of precision medicine, identifying tumor-selective biomarkers is a key to drug development. In addition, predictive biomarkers may serve as a guide to treatment decisions. In the pre-clinical studies leading to the development of ABBV-011, SEZ6 expression was found to correlate with treatment response (5, 59). Although corresponding analyses in clinical samples are awaited, this indicates a possible predictive value of SEZ6 expression, which can be feasibly assessed in tumor tissue by IHC (48). Considering the link to ASCL1 and the consistently increased expression in NE-high tumors, defining the transcriptional states associated with response may also hold potential as a predictive marker, and warrants further attention. It will be crucial to investigate biomarkers beyond target expression as predictive of response.

This review highlights several areas that need to be addressed in future research, including functional studies to discern whether SEZ6 has oncogenic activity, or mainly is reflective of cancer cells with a neuroendocrine profile. Furthermore, confirmatory studies are needed to establish the prognostic role of SEZ6, and to assess the potential impact of chemotherapy on SEZ6 expression. Despite limited available data, this novel target demonstrates promise as a therapeutic avenue for patients with few effective management options, and further clinical investigation is eagerly awaited.