A DLL3-targeted antibody-drug conjugate eradicates high-grade pulmonary neuroendocrine tumor-initiating cells in vivo Journal Article
| Authors: | Saunders, L. R.; Bankovich, A. J.; Anderson, W. C.; Aujay, M. A.; Bheddah, S.; Black, K.; Desai, R.; Escarpe, P. A.; Hampl, J.; Laysang, A.; Liu, D.; Lopez-Molina, J.; Milton, M.; Park, A.; Pysz, M. A.; Shao, H.; Slingerland, B.; Torgov, M.; Williams, S. A.; Foord, O.; Howard, P.; Jassem, J.; Badzio, A.; Czapiewski, P.; Harpole, D. H.; Dowlati, A.; Massion, P. P.; Travis, W. D.; Pietanza, M. C.; Poirier, J. T.; Rudin, C. M.; Stull, R. A.; Dylla, S. J. |
| Article Title: | A DLL3-targeted antibody-drug conjugate eradicates high-grade pulmonary neuroendocrine tumor-initiating cells in vivo |
| Abstract: | The high-grade pulmonary neuroendocrine tumors, small cell lung cancer (SCLC) and large cell neuroendocrine carcinoma (LCNEC), remain among the most deadly malignancies. Therapies that effectively target and kill tumor-initiating cells (TICs) in these cancers should translate to improved patient survival. Patient-derived xenograft (PDX) tumors serve as excellent models to study tumor biology and characterize TICs. Increased expression of delta-like 3 (DLL3) was discovered in SCLC and LCNEC PDX tumors and confirmed in primary SCLC and LCNEC tumors. DLL3 protein is expressed on the surface of tumor cells but not in normal adult tissues. A DLL3-targeted antibody-drug conjugate (ADC), SC16LD6.5, comprised of a humanized anti-DLL3 monoclonal antibody conjugated to a DNA-damaging pyrrolobenzodiazepine (PBD) dimer toxin, induced durable tumor regression in vivo across multiple PDX models. Serial transplantation experiments executed with limiting dilutions of cells provided functional evidence confirming that the lack of tumor recurrence after SC16LD6.5 exposure resulted from effective targeting of DLL3-expressing TICs. In vivo efficacy correlated with DLL3 expression, and responses were observed in PDX models initiated from patients with both limited and extensive-stage disease and were independent of their sensitivity to standard-of-care chemotherapy regimens. SC16LD6.5 effectively targets and eradicates DLL3-expressing TICs in SCLC and LCNEC PDX tumors and is a promising first-in-class ADC for the treatment of high-grade pulmonary neuroendocrine tumors. © 2015, American Association for the Advancement of Science. All rights reserved. |
| Keywords: | controlled study; protein expression; unclassified drug; human cell; cisplatin; drug efficacy; drug safety; nonhuman; outcome assessment; antineoplastic agent; binding affinity; mouse; animal tissue; cell viability; embryo; etoposide; cell protein; animal experiment; animal model; in vivo study; tumor xenograft; drug specificity; drug synthesis; monoclonal antibody; neuroendocrine tumor; gene expression regulation; cancer inhibition; drug mechanism; messenger rna; microarray analysis; tumor cell; single drug dose; cellular distribution; drug cytotoxicity; cross reaction; antigen binding; transcriptome; short hairpin rna; immunoglobulin g1 antibody; drug conjugation; concentration response; internalization; drug exposure; small cell lung cancer; large cell neuroendocrine carcinoma; cell surface; molecularly targeted therapy; antibody conjugate; pulmonary neuroendocrine tumor; toxin; human; female; priority journal; article; hek293 cell line; patient derived xenograft; antibody drug conjugate sc16ld6 5; delta like 3 protein; dna damaging damaging pyrrolobenzodiazepine dimer toxin; immunoglobulin g1 antibody ld6 5; monoclonal antibody sc16; tumor initiating cell |
| Journal Title: | Science Translational Medicine |
| Volume: | 7 |
| Issue: | 302 |
| ISSN: | 1946-6234 |
| Publisher: | American Association for the Advancement of Science |
| Date Published: | 2015-08-26 |
| Start Page: | 302ra136 |
| Language: | English |
| DOI: | 10.1126/scitranslmed.aac9459 |
| PROVIDER: | scopus |
| PUBMED: | 26311731 |
| PMCID: | PMC4934375 |
| DOI/URL: | |
| Notes: | Export Date: 2 October 2015 -- Source: Scopus |
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