Skip to main page content
U.S. flag

An official website of the United States government

Dot gov

The .gov means it’s official.
Federal government websites often end in .gov or .mil. Before sharing sensitive information, make sure you’re on a federal government site.

Https

The site is secure.
The https:// ensures that you are connecting to the official website and that any information you provide is encrypted and transmitted securely.

Access keys NCBI Homepage MyNCBI Homepage Main Content Main Navigation
. 2025 Sep 5:10.1158/1078-0432.CCR-25-2090.
doi: 10.1158/1078-0432.CCR-25-2090. Online ahead of print.

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

Emelie Gezelius  1 , Natasha Rekhtman  2 , Marina K Baine  3 , Charles M Rudin  3 , Alexander Drilon  2 , Alissa J Cooper  4
Affiliations

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

Emelie Gezelius et al. Clin Cancer Res. .

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.

PubMed Disclaimer

Conflict of interest statement

C.M. Rudin has consulted regarding oncology drug development with Amgen, AstraZeneca, Daiichi Sankyo, Hoffman-La Roche, Jazz and Novartis, serves on the scientific advisory boards of Auron, DISCO, and Earli, and has received royalty payments for licensing of DLL3-directed therapeutics. A. Drilon has the following disclosures: Honoraria: 14ner/Elevation Oncology, Amgen, Abbvie, AnHeart Therapeutics, ArcherDX, AstraZeneca, Beigene, BergenBio, Blueprint Medicines, Bristol Myers Squibb, Boehringer Ingelheim, Chugai Pharmaceutical, EcoR1, EMD Serono, Entos, Exelixis, Helsinn, Hengrui Therapeutics, Ignyta/Genentech/Roche, Janssen, Loxo/Bayer/Lilly, Merus, Monopteros, MonteRosa, Novartis, Nuvalent, Pfizer, Prelude, Regeneron, Repare RX, Springer Healthcare, Takeda/Ariad/Millenium, Treeline Bio, TP Therapeutics, Tyra Biosciences, Verastem, Zymeworks. Advisory Boards: Bayer, MonteRosa, Abbvie, EcoR1 Capital, LLC, Amgen, Helsinn, Novartis, Loxo/Lilly, AnHeart Therapeutics. Consulting: MonteRosa, Innocare, Boundless Bio, Treeline Bio, Nuvalent, 14ner/Elevation Oncology, Entos, Prelude, Bayer, Applied Pharmaceutical Science, Bristol Myers Squibb, Enlaza, Pfizer, Roche/Genetech, Nuvalent, Two River, Lilly/Loxo. Associated Research Paid to Institution: Foundation Medicine, GlaxoSmithKlein, Teva, Taiho, PharmaMar. Equity: mBrace, Treeline. Copyright: Copyright: Selpercatinib-Osimertinib (US 18/041,617, pending). Royalties: Wolters Kluwer, UpToDate. A. J. Cooper has received honoraria from MJH Life Sciences, Ideology Health, Intellisphere LLC, MedStar Health and CancerGRACE, and consulting fees from Gilead Sciences, Inc, Daiichi/Astra Zeneca, Novartis, BI, and Regeneron. She reports research funding to institution from Merck, Monte Rosa, AbbVie, Roche, Daiichi Sankyo, and Amgen. The other authors declare no conflicts of interest.

Figures

Figure 1:
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.
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.
Figure 3:
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.
Figure 4:
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.
Figure 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.
See this image and copyright information in PMC

References

    1. Kawasaki K, Rekhtman N, Quintanal-Villalonga A, Rudin CM. Neuroendocrine neoplasms of the lung and gastrointestinal system: convergent biology and a path to better therapies. Nat Rev Clin Oncol. 2023;20(1):16–32. - PubMed
    1. Horn L, Mansfield AS, Szczesna A, Havel L, Krzakowski M, Hochmair MJ, et al. First-Line Atezolizumab plus Chemotherapy in Extensive-Stage Small-Cell Lung Cancer. N Engl J Med. 2018;379(23):2220–9. - PubMed
    1. Paz-Ares L, Dvorkin M, Chen Y, Reinmuth N, Hotta K, Trukhin D, et al. Durvalumab plus platinum-etoposide versus platinum-etoposide in first-line treatment of extensive-stage small-cell lung cancer (CASPIAN): a randomised, controlled, open-label, phase 3 trial. Lancet. 2019;394(10212):1929–39. - PubMed
    1. Dingemans AC, Fruh M, Ardizzoni A, Besse B, Faivre-Finn C, Hendriks LE, et al. Small-cell lung cancer: ESMO Clinical Practice Guidelines for diagnosis, treatment and follow-up(☆). Ann Oncol. 2021;32(7):839–53. - PMC - PubMed
    1. Wiedemeyer WR, Gavrilyuk J, Schammel A, Zhao X, Sarvaiya H, Pysz M, et al. ABBV-011, A Novel, Calicheamicin-Based Antibody-Drug Conjugate, Targets SEZ6 to Eradicate Small Cell Lung Cancer Tumors. Mol Cancer Ther. 2022;21(6):986–98. - PMC - PubMed

LinkOut - more resources