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

Clin Cancer Res. 2021 Mar 1;27(5):1526-1537. doi: 10.1158/1078-0432.CCR-20-2845. Epub 2020 Nov 17.


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.

MeSH terms

  • Animals
  • Antibodies, Bispecific* / pharmacology
  • Antibodies, Monoclonal* / pharmacology
  • Antineoplastic Agents / pharmacology
  • Apoptosis
  • Cell Proliferation
  • Female
  • Gene Expression Regulation, Neoplastic* / drug effects
  • Humans
  • Intracellular Signaling Peptides and Proteins* / antagonists & inhibitors
  • Lung Neoplasms* / drug therapy
  • Lung Neoplasms* / immunology
  • Lung Neoplasms* / metabolism
  • Lung Neoplasms* / pathology
  • Membrane Proteins* / antagonists & inhibitors
  • Mice
  • Mice, Inbred NOD
  • Mice, SCID
  • Small Cell Lung Carcinoma* / drug therapy
  • Small Cell Lung Carcinoma* / immunology
  • Small Cell Lung Carcinoma* / metabolism
  • Small Cell Lung Carcinoma* / pathology
  • T-Lymphocytes* / drug effects
  • T-Lymphocytes* / immunology
  • Tumor Cells, Cultured
  • Xenograft Model Antitumor Assays


  • Antibodies, Bispecific
  • Antibodies, Monoclonal
  • Antineoplastic Agents
  • DLL3 protein, human
  • Intracellular Signaling Peptides and Proteins
  • Membrane Proteins
  • AMG 757