AMG 757, a Half-Life Extended, DLL3-Targeted Bispecific T-Cell Engager, Shows High Potency and Sensitivity in Preclinical Models of Small-Cell Lung Cancer

Abstract

Purpose: Small-cell lung cancer (SCLC) is an aggressive neuroendocrine tumor with a high relapse rate, limited therapeutic options, and poor prognosis. We investigated the antitumor activity of AMG 757, a half-life extended bispecific T-cell engager molecule targeting delta-like ligand 3 (DLL3)—a target that is selectively expressed in SCLC tumors, but with minimal normal tissue expression. Experimental Design: AMG 757 efficacy was evaluated in SCLC cell lines and in orthotopic and patient-derived xenograft (PDX) mouse SCLC models. Following AMG 757 administration, changes in tumor volume, pharmacodynamic changes in tumor-infiltrating T cells (TILs), and the spatial relationship between the appearance of TILs and tumor histology were examined. Tolerability was assessed in nonhuman primates (NHPs). Results: AMG 757 showed potent and specific killing of even those SCLC cell lines with very low DLL3 expression (<1,000 molecules per cell). AMG 757 effectively engaged systemically administered human T cells, induced T-cell activation, and redirected T cells to lyse tumor cells to promote significant tumor regression and complete responses in PDX models of SCLC and in orthotopic models of established primary lung SCLC and metastatic liver lesions. AMG 757 was well tolerated with no AMG 757-related adverse findings up to the highest tested dose (4.5 mg/kg weekly) in NHP. AMG 757 exhibits an extended half-life in NHP, which is projected to enable intermittent administration in patients. Conclusions: AMG 757 has a compelling safety and efficacy profile in preclinical studies making it a viable option for targeting DLL3-expressing SCLC tumors in the clinical setting.

PAX8 lineage-driven T cell engaging antibody for the treatment of high-grade serous ovarian cancer

“…The narrow therapeutic index of T cell bispecific antibodies has been a major challenge for the successful development of TCBs against solid tumor targets such as CEA, PSMA and HER2 [10][11][12] . Recent single agent clinical responses demonstrated by the anti-DLL3xCD3 (AMG757) in small cell lung cancer and by the anti-MUC16xCD3 (REGN4018) in advanced ovarian cancers have demonstrated clinical proof-of-concept for this modality in targets with tumor-restricted expression profiles similar to LYPD1 13,14 . Widespread use of immune checkpoint inhibitors has opened up the possibilities of combination therapy of TCBs with anti-PD-1/PD-L1 inhibitors in patients.…”

“…Despite these challenges, TCBs targeting tumor-restricted antigens are emerging as potent forms of immunotherapy in advanced-stage solid tumors of high unmet medical need. Recent single agent clinical responses were shown by the anti-DLL3xCD3 (AMG757) in small cell lung cancer and by the anti-MUC16xCD3 (REGN4018) in advanced ovarian cancers 13 , 14 .…”

“…www.nature.com/scientificreports/ responses were shown by the anti-DLL3xCD3 (AMG757) in small cell lung cancer and by the anti-MUC16xCD3 (REGN4018) in advanced ovarian cancers 13,14 .…”

Molecular Pathology of Pulmonary Large Cell Neuroendocrine Carcinoma: Novel Concepts and Treatments

“…Unfortunately, modest clinical activity with associated toxicities led to the discontinuation of Rova-T in later studies (75). Two other novel DLL3-targeted therapies are anti-DLL3/CD3 bispecific antibodies (AMG 757) and DLL3-binding chimeric antigen receptor-modified T cells (AMG 119) (76,77). Clinical evaluation of these therapies in SCLC patients is ongoing (NCT03319940 and NCT03392064).…”

Delta‐like canonical Notch ligand 3 as a potential therapeutic target in malignancies: A brief overview

“…Bispecific T‐cell engager is a novel immune treatment that redirects a patient’s T cells to kill tumor cells 21 . AMG 757 is a first‐in‐class, half‐life‐extended, BiTE molecule that activates T cells to reduce DLL3‐expressing tumor cells 22 . AMG 757 was effective against SCLC cell lines in vitro and resulted in significant tumor regression through T cell activation in both patient‐derived xenografts and orthotopic SCLC tumors in mouse models 22 .…”