Reference Detail

Ref Type

Poster

PMID

Authors

M. Giffin, K. Cooke, E. Lobenhofer, M. Friedrich,T. Raum, A. Coxon

Title

Targeting DLL3 with AMG 757, a BiTE® Antibody Construct, and AMG 119, a CAR-T, for the Treatment of SCLC

Journal	Vol	Issue	Date	Pages	Journal Short Title
Journal of Thoracic Oncology	13	10	2018

URL

https://doi.org/10.1016/j.jtho.2018.08.1826

Abstract Text

Background Small cell lung cancer (SCLC) is a highly aggressive neuroendocrine tumor with a poor prognosis and limited therapeutic options. Redirecting the potent cytotoxic potential of T cells via bi-specific T cell engager (BiTE®) antibody constructs and chimeric antigen receptor T cells (CAR-T) represents a promising new approach in the treatment of cancer, with durable complete responses observed in the clinic. Method Differential expression profiling of SCLC tumors and normal tissues was performed using RNAseq and immunohistochemistry. BiTE® and CAR scFv constructs were converted from fully human antibodies. BiTE® and CAR redirected T cell activity was evaluated in vitro and in vivo. Result Analysis of gene expression in SCLC tumors versus normal tissues identified Delta-Like Ligand 3 (DLL3) as a highly specific tumor associated antigen for SCLC. Expression of DLL3 in normal tissues was detected at very low levels in the brain, pituitary, and pancreatic islets, and showed a cytoplasmic staining pattern by IHC. We have developed a novel BiTE® antibody construct, AMG 757, with prolonged serum half-life relative to that of canonical BiTE® molecules. AMG 757 showed low picomolar potency against SCLC cell lines in vitro and also demonstrated significant inhibition of tumor growth in vivo. Pharmacokinetic analysis showed AMG 757 demonstrated a serum half-life predicted to support Q2W dosing in humans. Furthermore, AMG 757 was well tolerated in a repeat-dose 28-day GLP toxicology study, with no AMG 757-related adverse findings at doses as high as 4.5 mg/kg QW. Exposures were dose-proportional and with no evidence of tissue damage. We have also advanced AMG 119, a CAR-T targeting DLL3, into clinical development. AMG 119 demonstrated robust ablation of target cells in vitro and significant anti-tumor activity in an in vivo mouse model. AMG 119 CAR T cells showed robust cytokine production and proliferation when cultured in the presence of DLL3-positive cells, indicating appropriate T cell signaling as a function of antigen engagement. Conclusion The expression pattern of DLL3, with prevalent membranous expression in the majority of SCLC tumors and no detectable cell surface expression in normal cells, makes it an ideal target for BiTE®- and CAR-redirected T cell cytotoxicity. High potency against DLL3-positive tumor cells, coupled with an excellent preclinical safety profile suggest that AMG 119 and AMG 757 may provide a new therapeutic option for SCLC patients with DLL3-positive tumors. AMG 757 (NCT03319940) and AMG 119 (NCT03392064) are currently enrolling in Phase 1 studies for the treatment of relapsed/refractory SCLC.

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Molecular Profile	Treatment Approach

Gene Name	Source	Synonyms	Protein Domains	Gene Description	Gene Role

Therapy Name	Drugs	Efficacy Evidence	Clinical Trials
AMG 119	AMG 119	0	0

Drug Name	Trade Name	Synonyms	Drug Classes	Drug Description
AMG 119		AMG-119\|AMG119		AMG 119 are autologous T-cells that have been engineered to express a chimeric antigen receptor (CAR) that targets DLL3, potentially resulting in decreased tumor cell proliferation and reduced tumor growth (J of Thoracic Oncology. 2018, 13(Supplement), S971. P3.12-03).

Gene	Variant	Impact	Protein Effect	Variant Description	Associated with drug Resistance

Molecular Profile	Indication/Tumor Type	Response Type	Therapy Name	Approval Status	Evidence Type	Efficacy Evidence	References