SEZ6 ADC Drug Development Screening Model – SEZ6 Overexpression Cell Lines
Kyinno Biotechnology, Inc.
A preclinical CRO drives progress in cancer research and drug discovery
On October 29, 2024, the U.S. Food and Drug Administration (FDA) granted orphan drug designation to ABBV-706, developed by AbbVie, for the treatment of small cell lung cancer (SCLC). This designation recognizes the potential value of ABBV-706 in treating this rare and highly aggressive cancer, while also further confirming SEZ6 as one of the effective therapeutic targets for SCLC.
Small cell lung cancer (SCLC) accounts for approximately 15% of all lung cancers. It is highly malignant, progresses rapidly, is prone to distant metastasis, and often relapses after treatment, making it particularly challenging to treat. The treatment options for SCLC are relatively limited, primarily relying on chemotherapy and radiotherapy. However, these methods offer limited survival benefits to patients, resulting in extremely poor prognoses. The effectiveness and long-term efficacy of these treatments still need improvement. A major challenge in treating SCLC is the lack of suitable therapeutic breakthroughs.
Using RNA sequencing (RNA-seq) data from primary and xenograft SCLC samples, AbbVie discovered through RNA-seq and immunohistochemistry that Seizure-related 6 homolog (SEZ6) is widely expressed in SCLC but minimally expressed in normal tissues. Therefore, SEZ6 may be an effective target for SCLC.
Based on the specific high expression of SEZ6 in tumors, AbbVie developed an ADC targeting SEZ6, ABBV-011, indicated for small cell lung cancer (public patent: WO2013126810A). This ADC uses calicheamicin as the toxin, with a drug-to-antibody ratio (DAR) of 2 and a non-degradable linker. The ADC entered Phase I clinical trials in 2019 (NCT03639194), but unfortunately, the pipeline was discontinued by AbbVie last year.
However, the good news is that ABV-706 is still under clinical development and is the only known SEZ6-targeting ADC currently in progress. In February 2024, AbbVie disclosed the latest SEZ6 ADC, ABV-706 (public patent: WO2024042497A1). The patent describes a structurally novel topoisomerase 1 inhibitor (Top1i) with significantly superior anti-proliferative activity compared to SN-38, intended for the treatment of advanced solid tumors, including small cell lung cancer (SCLC), central nervous system (CNS) tumors, and neuroendocrine carcinoma (NEC).
SEZ6 is a protein highly expressed in the central nervous system, and its dysfunction is closely associated with various neurological disorders, including epilepsy, autism spectrum disorder, and schizophrenia. SEZ6 is involved in regulating signal transmission between neurons and influences the formation and development of neural networks. In the context of neurological diseases, knockout of SEZ6 in mice promotes the formation of short, polysynaptic connections. SEZ6 is a substrate of BACE1, and soluble SEZ6 in cerebrospinal fluid can serve as a biomarker for Alzheimer's disease. As a tumor-specific marker, SEZ6 is highly expressed in neuroendocrine tumor tissues. Immunohistochemical analysis of clinical specimens shows that SEZ6 is highly expressed in small cell lung cancer, with expression levels significantly higher than in normal tissues. In tumor tissue samples from 174 SCLC patients, approximately 70% showed positive SEZ6 expression, making it an important target for developing novel therapeutic strategies.
To support the development of SEZ6-related drugs, Kangyuan BioCreation has constructed various SEZ6 overexpression cell models, which can be used for in vitro screening of SEZ6 inhibitors and antibody drugs. Below is a partial list of SEZ6 overexpression cell lines. Please contact us for more information.
SEZ6 Cell Line List:
Flow Cytometry Validation of SEZ6 Expression
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References:
1. Wiedemeyer WR, Gavrilyuk J, Schammel A, Zhao X, Sarvaiya H, Pysz M, Gu C, You M, Isse K, Sullivan T, French D, Lee C, Dang AT, Zhang Z, Aujay M, Bankovich AJ, Vitorino P. ABBV-011, A Novel, Calicheamicin-Based Antibody-Drug Conjugate, Targets SEZ6 to Eradicate Small Cell Lung Cancer Tumors. Mol Cancer Ther. 2022 Jun 1;21(6):986-998.
2. Belluomini L, Sposito M, Avancini A, Insolda J, Milella M, Rossi A, Pilotto S. Unlocking New Horizons in Small-Cell Lung Cancer Treatment: The Onset of Antibody-Drug Conjugates. Cancers (Basel). 2023 Nov 10;15(22):5368.
3. Meng Y, Wang X, Yang J, Zhu M, Yu M, Li L, Liang Y, Kong F. Antibody-drug conjugates treatment of small cell lung cancer: advances in clinical research. Discov Oncol. 2024 Aug 1;15(1):327.