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Michael Giffin



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    P3.12 - Small Cell Lung Cancer/NET (Not CME Accredited Session) (ID 978)

    • Event: WCLC 2018
    • Type: Poster Viewing in the Exhibit Hall
    • Track:
    • Presentations: 1
    • Moderators:
    • Coordinates: 9/26/2018, 12:00 - 13:30, Exhibit Hall
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      P3.12-03 - Targeting DLL3 with AMG 757, a BiTE® Antibody Construct, and AMG 119, a CAR-T, for the Treatment of SCLC (ID 14539)

      12:00 - 13:30  |  Presenting Author(s): Michael Giffin

      • Abstract
      • Slides

      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. a9ded1e5ce5d75814730bb4caaf49419 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.
      4c3880bb027f159e801041b1021e88e8 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.
      8eea62084ca7e541d918e823422bd82e 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. 6f8b794f3246b0c1e1780bb4d4d5dc53

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