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.

High-Affinity Internalizing Human scFv-Fc Antibody for Targeting FGFR1-Overexpressing Lung Cancer

“…Recently, the ADC rovalpituzumab tesirine (Rova-T; SC16LD6.5) targeting DLL3 (Delta-like 3 protein) antigen overexpressed in patients with SCLC showed encouraging results in preclinical and phase I studies (NCT01901653; ref. 32).…”

A New Class of Antibody–Drug Conjugates with Potent DNA Alkylating Activity

“…For example, ADCs carrying the potent DNA interacting agent calicheamicin are tolerated by humans only at very low doses and one such ADC, gemtuzumab ozogamicin, was withdrawn from the market due to a narrow therapeutic index and related safety concerns (15). ADCs of pyrrolobenzodiazepine (PBD) dimers, potent DNA cross-linkers, have recently been advanced into clinical evaluation (16)(17)(18). These ADCs incorporate derivatives of the PBD dimer SJG-136, a highly toxic small molecule with a maximally tolerated dose (MTD) of $1.2 mg/kg in humans (19).…”

Entwicklung Pyrrolobenzodiazepin(PBD)‐haltiger Antikörper‐Wirkstoff‐Konjugate (ADCs) ausgehend von Anthramycin

“…Diese Strategie wurde zuvor in Patenten von Genentech Inc. und Spirogen Ltd. beschrieben. [108] In präklinischen Studien [110] mit dem nackten Antikçrper SC16 wurde weder gegenüber der DLL3-null HEK-293T-noch gegenüber der DLL3-exprimierenden HEK-293T.hDLL3-Zelllinie Zytotoxizität festgestellt, während das PBD-Dimer allein und das komplette ADC (Rova-T) beide eine deutliche Zytotoxizität mit EC 50 -Werten von 46.9 bzw. 7.8 pm gegenüber den HEK-293T.hDLL3-Zellen zeigten.…”