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.
authors: Stemcentrx Inc., South San Francisco, CA 94080, USA.
authors: Laura R
authors: LR
authors: Saunders
authors: Stemcentrx Inc., South San Francisco, CA 94080, USA.
authors: Alexander J
authors: AJ
authors: Bankovich
authors: Stemcentrx Inc., South San Francisco, CA 94080, USA.
authors: Wade C
authors: WC
authors: Anderson
authors: Stemcentrx Inc., South San Francisco, CA 94080, USA.
authors: Monette A
authors: MA
authors: Aujay
authors: Stemcentrx Inc., South San Francisco, CA 94080, USA.
authors: Sheila
authors: S
authors: Bheddah
authors: Stemcentrx Inc., South San Francisco, CA 94080, USA.
authors: KristenAnn
authors: K
authors: Black
authors: Stemcentrx Inc., South San Francisco, CA 94080, USA.
authors: Radhika
authors: R
authors: Desai
authors: Stemcentrx Inc., South San Francisco, CA 94080, USA.
authors: Paul A
authors: PA
authors: Escarpe
authors: Stemcentrx Inc., South San Francisco, CA 94080, USA.
authors: Johannes
authors: J
authors: Hampl
authors: Stemcentrx Inc., South San Francisco, CA 94080, USA.
authors: Amy
authors: A
authors: Laysang
authors: Stemcentrx Inc., South San Francisco, CA 94080, USA.
authors: David
authors: D
authors: Liu
authors: Stemcentrx Inc., South San Francisco, CA 94080, USA.
authors: Javier
authors: J
authors: Lopez-Molina
authors: Stemcentrx Inc., South San Francisco, CA 94080, USA.
authors: Milly
authors: M
authors: Milton
authors: Stemcentrx Inc., South San Francisco, CA 94080, USA.
authors: Albert
authors: A
authors: Park
authors: Stemcentrx Inc., South San Francisco, CA 94080, USA.
authors: Marybeth A
authors: MA
authors: Pysz
authors: Stemcentrx Inc., South San Francisco, CA 94080, USA.
authors: Hui
authors: H
authors: Shao
authors: Stemcentrx Inc., South San Francisco, CA 94080, USA.
authors: Brian
authors: B
authors: Slingerland
authors: Stemcentrx Inc., South San Francisco, CA 94080, USA.
authors: Michael
authors: M
authors: Torgov
authors: Stemcentrx Inc., South San Francisco, CA 94080, USA.
authors: Samuel A
authors: SA
authors: Williams
authors: Stemcentrx Inc., South San Francisco, CA 94080, USA.
authors: Orit
authors: O
authors: Foord
authors: Spirogen (a member of the AstraZeneca Group), London W2 6BD, UK.
authors: Philip
authors: P
authors: Howard
authors: Medical University of Gdańsk, Gdańsk 82-300, Poland.
authors: Jacek
authors: J
authors: Jassem
authors: Medical University of Gdańsk, Gdańsk 82-300, Poland.
authors: Andrzej
authors: A
authors: Badzio
authors: Medical University of Gdańsk, Gdańsk 82-300, Poland.
authors: Piotr
authors: P
authors: Czapiewski
authors: Duke University Medical Cancer, Durham, NC 27710, USA.
authors: David H
authors: DH
authors: Harpole
authors: Case Western Reserve University and University Hospitals Seidman Cancer Center, Cleveland, OH 44106, USA.
authors: Afshin
authors: A
authors: Dowlati
authors: Thoracic Program, Vanderbilt-Ingram Cancer Center, Tennessee Valley Healthcare Systems, Nashville Campus, Nashville, TN 37232, USA.
authors: Pierre P
authors: PP
authors: Massion
authors: Memorial Sloan Kettering Cancer Center, New York, NY 10065, USA.
authors: William D
authors: WD
authors: Travis
authors: Memorial Sloan Kettering Cancer Center, New York, NY 10065, USA. Weill Cornell Medical College, New York, NY 10065, USA.
authors: M Catherine
authors: MC
authors: Pietanza
authors: Memorial Sloan Kettering Cancer Center, New York, NY 10065, USA. Weill Cornell Medical College, New York, NY 10065, USA.
authors: J T
authors: JT
authors: Poirier
authors: Memorial Sloan Kettering Cancer Center, New York, NY 10065, USA.
authors: Charles M
authors: CM
authors: Rudin
authors: Stemcentrx Inc., South San Francisco, CA 94080, USA.
authors: Robert A
authors: RA
authors: Stull
authors: Stemcentrx Inc., South San Francisco, CA 94080, USA. scott.dylla@stemcentrx.com.
authors: Scott J
authors: SJ
authors: Dylla
mesh_terms: D000818:Animals; D000911:Antibodies, Monoclonal / Q000276:immunology*; D000970:Antineoplastic Agents / Q000627:therapeutic use*; D005260:Female; D006801:Humans; D018796:Immunoconjugates / Q000627:therapeutic use*; D047908:Intracellular Signaling Peptides and Proteins / Q000276:immunology* / Q000378:metabolism; D008175:Lung Neoplasms / Q000188:drug therapy* / Q000378:metabolism; D008565:Membrane Proteins / Q000276:immunology* / Q000378:metabolism; D051379:Mice; D016688:Mice, Inbred NOD; D016513:Mice, SCID; D018358:Neuroendocrine Tumors / Q000188:drug therapy* / Q000378:metabolism; D023041:Xenograft Model Antitumor Assays
chemical_list: D000911:Antibodies, Monoclonal; D000970:Antineoplastic Agents; C496666:DLL3 protein, human; D018796:Immunoconjugates; D047908:Intracellular Signaling Peptides and Proteins; D008565:Membrane Proteins