2. Academic Validation
  3. 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

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.
Michael J Giffin # 1,  Keegan Cooke # 1,  Edward K Lobenhofer 2,  Juan Estrada 1,  Jinghui Zhan 1,  Petra Deegen 3,  Melissa Thomas 4,  Christopher M Murawsky 5,  Jonathan Werner 2,  Siyuan Liu 1,  Fei Lee 6,  Oliver Homann 7,  Matthias Friedrich 3,  Joshua T Pearson 8,  Tobias Raum 9,  Yajing Yang 1,  Sean Caenepeel 1,  Jennitte Stevens 10,  Pedro J Beltran 1,  Jude Canon 1,  Angela Coxon 1,  Julie M Bailis 11,  Paul E Hughes 12
Affiliations

Affiliations

  • 1 Oncology Research, Amgen Research, Thousand Oaks, California.
  • 2 Translational Safety & Bioanalytical Sciences, Amgen Research, Thousand Oaks, California.
  • 3 Translational Safety & Bioanalytical Sciences, Amgen Research (Munich) GmbH, Munich, Germany.
  • 4 Therapeutic Discovery, Amgen Research, South San Francisco, California.
  • 5 Therapeutic Discovery, Amgen Research, Burnaby, British Columbia, Canada.
  • 6 Oncology Research, Amgen Research, South San Francisco, California.
  • 7 Genome Analysis Unit, Amgen Research, South San Francisco, California.
  • 8 Pharmacokinetics & Drug Metabolism, Amgen Research, South San Francisco, California.
  • 9 Therapeutic Discovery, Amgen Research (Munich) GmbH, Munich, Germany.
  • 10 Therapeutic Discovery, Amgen Research, Thousand Oaks, California.
  • 11 Oncology Research, Amgen Research, South San Francisco, California. phughes@amgen.com jbailis@amgen.com.
  • 12 Oncology Research, Amgen Research, Thousand Oaks, California. phughes@amgen.com jbailis@amgen.com.
  • # Contributed equally.
PMID: 33203642 DOI: 10.1158/1078-0432.CCR-20-2845
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.

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