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AMG 757, a Half-Life Extended, DLL3-Targeted Bispecific T-Cell Engager, Shows High Potency and Sensitivity in
Michael J Giffin1, Keegan Cooke1, Edward K Lobenhofer2
1Oncology Research, Amgen Research, Thousand Oaks, California.
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.
Insights
AMG 757, a novel bispecific T-cell engager, demonstrates potent antitumor activity against small-cell lung cancer (SCLC) by targeting DLL3. This promising therapy shows significant tumor regression and tolerability in preclinical models.
Area of Science:
- Oncology
- Immunotherapy
- Drug Development
Background:
- Small-cell lung cancer (SCLC) is an aggressive neuroendocrine tumor with limited treatment options and poor prognosis.
- Delta-like ligand 3 (DLL3) is selectively expressed in SCLC tumors, making it a promising therapeutic target.
- There is a critical need for novel therapeutic strategies to improve outcomes for SCLC patients.
Purpose of the Study:
- To investigate the antitumor activity and safety of AMG 757, a bispecific T-cell engager targeting DLL3.
- To evaluate AMG 757's efficacy in preclinical SCLC models, including cell lines and xenografts.
- To assess the tolerability and pharmacokinetic profile of AMG 757.
Main Methods:
- AMG 757 efficacy was assessed in SCLC cell lines and orthotopic/patient-derived xenograft (PDX) mouse models.
- Tumor volume, T-cell infiltration, and tumor histology were analyzed post-AMG 757 administration.
- Tolerability was evaluated in nonhuman primates (NHPs).
Main Results:
- AMG 757 demonstrated potent and specific killing of SCLC cells, including those with low DLL3 expression.
- The drug effectively engaged T cells, induced their activation, and promoted significant tumor regression in preclinical models.
- AMG 757 was well tolerated in NHPs, with an extended half-life supporting intermittent administration.
Conclusions:
- AMG 757 exhibits a compelling safety and efficacy profile in preclinical studies.
- This agent is a viable option for targeting DLL3-expressing SCLC tumors in clinical settings.
- Further clinical investigation of AMG 757 for SCLC treatment is warranted.
