Neutralizing complement resistance improves cell-mediated killing (CDCC) of HER2 positive breast cancer cells by Trastuzumab and Pertuzumab

Abstract

Event Abstract Back to Event Neutralizing complement resistance improves cell-mediated killing (CDCC) of HER2 positive breast cancer cells by Trastuzumab and Pertuzumab Srinivas Mamidi1, Simon Hoene1 and Michael Kirschfink1* 1 University of Heidelberg, Institute for Immunology, Germany The therapeutic potential of anti-cancer mAbs is hampered by the ability of malignant cells to acquire resistance to complement, primarily by the over-expression of membrane complement regulatory proteins (mCRPs) such as CD46, CD55 and CD59. Trastuzumab and Pertuzumab are anti-HER2 monoclonal antibodies approved for the treatment of HER2-positive breast cancers, which exert only minor complement-mediated cytotoxicity (CDC). Upon opsonisation of tumor cells with the C3 split product iC3b, complement receptor 3 (CD11b/CD18) on NK cells and macrophages mediates complement-dependent cellular cytotoxicity (CDCC). Here, we investigated whether treatment of HER2 positive tumor cells with trastuzumab and pertuzumab not only leads to direct destruction by CDC but also induces CDCC and if silencing of mCRPs with siRNA enhances cell-mediated cytotoxicity. Small interfering RNAs (siRNAs), which are chemically stabilized by 2´-O-methyl sugar modifications, were encapsulated in liposomes (AtuPLEX) for delivery to Her2/neu high expressing BT474 breast tumor cells to knockdown synthesis of CD46, CD55 and CD59. Upon mCRPs knock down, CDC was significantly increased when BT474 tumor cells were treated with both trastuzumab and pertuzumab. Complement-induced apoptosis and caspase activation was augmented if mCRPs were neutralized in tumor cells. Incubation of tumor cells with both antibodies also led to increased C3 deposition (opsonization), and further augmented tumor cell killing by M1 and M2 macrophages. Furthermore, incubation of mCRP neutralized BT474 cells with PBL or NK92 cells further augmented cell-mediated cytotoxicity. Thus, the combination of both trastuzumab and pertuzumab induces CDCC and neutralization of complement regulators further enhances their anti-tumor effects. Keywords: Complement resistance, siRNA, Immunotherapy, trastuzumab, Pertuzumab Conference: 15th International Congress of Immunology (ICI), Milan, Italy, 22 Aug - 27 Aug, 2013. Presentation Type: Abstract Topic: Translational immunology and immune intervention Citation: Mamidi S, Hoene S and Kirschfink M (2013). Neutralizing complement resistance improves cell-mediated killing (CDCC) of HER2 positive breast cancer cells by Trastuzumab and Pertuzumab. Front. Immunol. Conference Abstract: 15th International Congress of Immunology (ICI). doi: 10.3389/conf.fimmu.2013.02.00959 Copyright: The abstracts in this collection have not been subject to any Frontiers peer review or checks, and are not endorsed by Frontiers. They are made available through the Frontiers publishing platform as a service to conference organizers and presenters. The copyright in the individual abstracts is owned by the author of each abstract or his/her employer unless otherwise stated. Each abstract, as well as the collection of abstracts, are published under a Creative Commons CC-BY 4.0 (attribution) licence (https://creativecommons.org/licenses/by/4.0/) and may thus be reproduced, translated, adapted and be the subject of derivative works provided the authors and Frontiers are attributed. For Frontiers’ terms and conditions please see https://www.frontiersin.org/legal/terms-and-conditions. Received: 26 Jun 2013; Published Online: 22 Aug 2013. * Correspondence: Prof. Michael Kirschfink, University of Heidelberg, Institute for Immunology, Heidelberg, Germany, kirschfink@uni-hd.de Login Required This action requires you to be registered with Frontiers and logged in. To register or login click here. Abstract Info Abstract The Authors in Frontiers Srinivas Mamidi Simon Hoene Michael Kirschfink Google Srinivas Mamidi Simon Hoene Michael Kirschfink Google Scholar Srinivas Mamidi Simon Hoene Michael Kirschfink PubMed Srinivas Mamidi Simon Hoene Michael Kirschfink Related Article in Frontiers Google Scholar PubMed Abstract Close Back to top Javascript is disabled. Please enable Javascript in your browser settings in order to see all the content on this page.