Lipoplex mediated silencing of membrane regulators (CD46, CD55 and CD59) enhances complement-dependent anti-tumor activity of trastuzumab and pertuzumab

• Verfasst von: Mamidi, Srinivas [VerfasserIn]
• Verfasst von: Cinci, Marc L. [VerfasserIn]
• Verfasst von: Hasmann, Max [VerfasserIn]
• Verfasst von: Fehring, Volker [VerfasserIn]
• Verfasst von: Kirschfink, Michael [VerfasserIn]
• Titel: Lipoplex mediated silencing of membrane regulators (CD46, CD55 and CD59) enhances complement-dependent anti-tumor activity of trastuzumab and pertuzumab
• Verf.angabe: Srinivas Mamidi, Marc Cinci, Max Hasmann, Volker Fehring, Michael Kirschfink
• E-Jahr: 2013
• Jahr: 20 February 2013
• Umfang: 15 S.
• Teil: volume:7
• Teil: year:2013
• Teil: number:3
• Teil: month:06
• Teil: pages:580-594
• Teil: extent:15
• Fussnoten: Gesehen am 17.06.2021
• Titel Quelle: Enthalten in: Molecular oncology
• Ort Quelle: Hoboken, NJ : John Wiley & Sons, Inc., 2007
• Jahr Quelle: 2013
• Band/Heft Quelle: 7(2013), 3 vom: Juni, Seite 580-594
• ISSN Quelle: 1878-0261
• DOI: doi:10.1016/j.molonc.2013.02.011
• Datenträger: Online-Ressource
• Sprache: eng
• Sach-SW: Complement regulatory proteins
• Sach-SW: Complement resistance
• Sach-SW: Lipoplex
• Sach-SW: Pertuzumab
• Sach-SW: siRNA
• Sach-SW: Trastuzumab
• K10plus-PPN: 1760776033

Abstract

The therapeutic potential of anticancer antibodies is limited by the resistance of tumor cells to complement-mediated attack, primarily through the over-expression of membrane complement regulatory proteins (mCRPs: CD46, CD55 and CD59). Trastuzumab, an anti- HER2 monoclonal antibody, approved for the treatment of HER2-positive breast and gastric cancers, exerts only minor complement-mediated cytotoxicity (CDC). Pertuzumab is a novel anti-HER2 monoclonal antibody, which blocks HER2 dimerization with other ligand-activated HER family members. Here, we explored the complement-mediated anti-tumor effects of trastuzumab and pertuzumab on HER2-positive tumor cells of various histological origins. Delivery of chemically stabilized anti-mCRP siRNAs using cationic lipoplexes, AtuPLEXes, to HER2-over-expressing BT474, SK-BR-3 (breast), SKOV3 (ovarian) and Calu-3 (lung) cancer cells reduced mCRPs expression by 85-95%. Knockdown of individual complement regulators variably led to increased CDC only upon combined treatment with trastuzumab and pertuzumab. The combined down-regulation of all the three regulators augmented CDC by 48% in BT474, 46% in SK-BR-3 cells, 78% in SKOV3 cells and by 30% in Calu-3 cells and also increased complement-induced apoptosis and caspase activity on mCRP neutralized tumor cells. In addition, antibody-induced C3 opsonization of tumor cells was significantly enhanced after mCRP silencing and further augmented tumor cell killing by macrophages. Our findings suggest that siRNA-induced inhibition of complement regulator expression clearly enhances complement- and macrophage-mediated anti-tumor activity of trastuzumab and pertuzumab on HER2-positive tumor cells. Thus - if selectively targeted to the tumor - siRNA-induced inhibition of complement regulation may serve as an innovative strategy to potentiate the efficacy of antibody-based immunotherapy.