DESTINY-Breast07: Preclinical Results (Results as of July 1, 2022 DCO)
T-DXd Internalization1
Live cell imaging was performed to assess the effects on T-DXd internalization using pH-dependent fluorescently labelled T-DXd. T-DXd was more rapidly and effectively internalized when combined with pertuzumab.1
Study Drug Internalization in the BT-474 Breast Cancer Cell Line.1,a
Study Drug Internalization in the BT-474 Breast Cancer Cell Line.1,a
![<p>Study Drug Internalization in the BT-474 Breast Cancer Cell Line.<span class="tooltip"><span class="tooltip-text"><sup>1</sup></span><span class="tooltip-content" style="display: none;"><span>1. Hamilton EP, Jhaveri KL, Loi S, et al. Dose-expansion study of trastuzumab deruxtecan as monotherapy or combined with pertuzumab in patients with metastatic human epidermal growth factor receptor-2 positive (HER2+) breast cancer in DESTINY-Breast07 (DB-07) [poster]. Poster presented at: San Antonio Breast Cancer Symposium (SABCS) 2022 Annual Meeting; December 6-10,2022; San Antonio, Texas. Poster PD18-11.</span></span></span><sup>,a</sup> </p>](/content/dam/intelligentcontent/docuvera/assets/global/trastuzumab-deruxtecan/325e86bc-2a1f-401a-b8d6-fa304896a85b/12dd433a-7992-480d-a346-fcfdeac115c2.png)
aInternalization rate was measured by pHrodo with labeled T-DXd, pertuzumab, IgG non-targeting control, and CD71 positive control. Combination arm is combination of labeled T-DXd and unlabeled pertuzumab.
HER2 Signaling1
Total and phosphorylated HER2 levels and downstream substrates were evaluated by immunoblot to assess the effects of T-DXd and/or pertuzumab on HER2 signaling. Immunoblotting of cell lysates demonstrated a greater reduction in total HER2 and HER2 signaling in response to combination treatment than with T-DXd or pertuzumab alone.1
Cell Lysate Immunoblotting Trafficking Index.1,a,b
Cell Lysate Immunoblotting Trafficking Index.1,a,b
![<p>Cell Lysate Immunoblotting Trafficking Index.<span class="tooltip"><span class="tooltip-text"><sup>1</sup></span><span class="tooltip-content" style="display: none;"><span>1. Hamilton EP, Jhaveri KL, Loi S, et al. Dose-expansion study of trastuzumab deruxtecan as monotherapy or combined with pertuzumab in patients with metastatic human epidermal growth factor receptor-2 positive (HER2+) breast cancer in DESTINY-Breast07 (DB-07) [poster]. Poster presented at: San Antonio Breast Cancer Symposium (SABCS) 2022 Annual Meeting; December 6-10,2022; San Antonio, Texas. Poster PD18-11.</span></span></span><sup>,a,b</sup></p>](/content/dam/intelligentcontent/docuvera/assets/global/trastuzumab-deruxtecan/325e86bc-2a1f-401a-b8d6-fa304896a85b/0f8a01ea-1e23-4bb9-b657-ed2ce28acac7.png)
Note: pHrodo is a pH-sensitive dye developed by Thermo Fisher used to measure intracellular pH in live cells.
aHER2 and phosphorylated HER2 levels were measured by western blot analysis after 24-hour treatment of MCF10A cells overexpressing HER2 (MCF10A-HER2 WT) with IgG, T-DXd, pertuzumab, and the combination
bInternalization rate was measured by live imaging of pHrodo-labeled T-DXd combined with either unlabeled pertuzumab or with the endocytosis inhibitor dynasore
Abbreviations
CD71 = transferrin receptor
;DCO = data cut-off
;DMSO = dimethyl sulfoxide
;HER2 = human epidermal growth factor receptor 2
;IgG = Immunoglobulin G
;pHER2 = phosphorylated human epidermal growth factor receptor 2
;T-DXd = trastuzumab deruxtecan
;WT = wild-type
References
1. Hamilton EP, Jhaveri KL, Loi S, et al. Dose-expansion study of trastuzumab deruxtecan as monotherapy or combined with pertuzumab in patients with metastatic human epidermal growth factor receptor-2 positive (HER2+) breast cancer in DESTINY-Breast07 (DB-07) [poster]. Poster presented at: San Antonio Breast Cancer Symposium (SABCS) 2022 Annual Meeting; December 6-10,2022; San Antonio, Texas. Poster PD18-11.
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Document ID: 325e86bc-2a1f-401a-b8d6-fa304896a85b
Last updated: 14-February-2023
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