title: Photoimmunotheranostic agents for triple-negative breast cancer diagnosis and therapy that can be activated on demand.
abstract: Triple-negative breast cancer (TNBC) is a heterogeneous disease in which the tumors do not express estrogen receptor (ER), progesterone receptor (PgR) or human epidermal growth factor receptor 2 (HER2). Classical receptor-targeted therapies such as tamoxifen or trastuzumab are therefore unsuitable and combinations of surgery, chemotherapy and/or radiotherapy are required. Photoimmunotheranostics is a minimally invasive approach in which antibodies deliver nontoxic photosensitizers that emit light to facilitate diagnosis and produce cytotoxic reactive oxygen species to induce apoptosis and/or necrosis in cancer cells. We developed a panel of photoimmunotheranostic agents against three TNBC-associated cell surface antigens. Antibodies against epidermal growth factor receptor (EGFR), epithelial cell adhesion molecule (EpCAM) and chondroitin sulfate proteoglycan 4 (CSPG4) were conjugated to the highly potent near-infrared imaging agent/photosensitizer IRDye®700DX phthalocyanine using SNAP-tag technology achieving clear imaging in both breast cancer cell lines and human biopsies and highly potent phototherapeutic activity with IC50values of 62-165 nM against five different cell lines expressing different levels of EGFR, EpCAM and CSPG4. A combination of all three reagents increased the therapeutic activity against TNBC cells by up to 40%.
authors.affiliation: Department of Experimental Medicine and Immunotherapy, Institute of Applied Medical Engineering, Helmholtz-Institute for Biomedical Engineering, 52074 Aachen, Germany.
authors.forename: Manal
authors.initials: M
authors.lastname: Amoury
authors.affiliation: Department of Gynecology and Obstetrics, University Medical Center Schleswig-Holstein, 24105 Kiel, Germany.
authors.forename: Dirk
authors.initials: D
authors.lastname: Bauerschlag
authors.affiliation: Department of Gynecology and Obstetrics, University Hospital RWTH Aachen, 52074 Aachen, Germany.
authors.forename: Felix
authors.initials: F
authors.lastname: Zeppernick
authors.affiliation: Department of Dermatology, University Hospital RWTH Aachen, 52074 Aachen, Germany.
authors.forename: Verena
authors.initials: V
authors.lastname: von Felbert
authors.affiliation: Department of Experimental Medicine and Immunotherapy, Institute of Applied Medical Engineering, Helmholtz-Institute for Biomedical Engineering, 52074 Aachen, Germany.
authors.forename: Nina
authors.initials: N
authors.lastname: Berges
authors.affiliation: Fraunhofer Institute for Molecular Biology and Applied Ecology IME, 52074 Aachen, Germany.
authors.forename: Stefano
authors.initials: S
authors.lastname: Di Fiore
authors.affiliation: Department of Gynecology and Obstetrics, University Hospital RWTH Aachen, 52074 Aachen, Germany.
authors.forename: Isabell
authors.initials: I
authors.lastname: Mintert
authors.affiliation: Department of Nuclear Medicine, University Hospital RWTH Aachen, 52074 Aachen, Germany.
authors.forename: Andreas
authors.initials: A
authors.lastname: Bleilevens
authors.affiliation: Department of Gynecology and Obstetrics, University Medical Center Schleswig-Holstein, 24105 Kiel, Germany.
authors.forename: Nicolai
authors.initials: N
authors.lastname: Maass
authors.affiliation: Department of Gynecology and Obstetrics, University Hospital Schleswig-Holstein, 23538 Lübeck, Germany.
authors.forename: Karen
authors.initials: K
authors.lastname: Bräutigam
authors.affiliation: Department of Gynecology and Obstetrics, University Hospital RWTH Aachen, 52074 Aachen, Germany.
authors.forename: Ivo
authors.initials: I
authors.lastname: Meinhold-Heerlein
authors.affiliation: Department of Gynecology and Obstetrics, University Hospital RWTH Aachen, 52074 Aachen, Germany.
authors.forename: Elmar
authors.initials: E
authors.lastname: Stickeler
authors.affiliation: Department of Pharmaceutical Product Development, Fraunhofer Institute for Molecular Biology and Applied Ecology IME, 52074 Aachen, Germany.|Current address: Institute of Infectious Disease and Molecular Medicine (IDM), Department of Integrative Biomedical Sciences, Faculty of Health Sciences, University of Cape Town, Cape Town 7925, South Africa.
authors.forename: Stefan
authors.initials: S
authors.lastname: Barth
authors.affiliation: Fraunhofer Institute for Molecular Biology and Applied Ecology IME, 52074 Aachen, Germany.|Institute of Molecular Biotechnology, RWTH Aachen University, 52074 Aachen, Germany.
authors.forename: Rainer
authors.initials: R
authors.lastname: Fischer
authors.affiliation: Department of Gynecology and Obstetrics, University Hospital RWTH Aachen, 52074 Aachen, Germany.
authors.forename: Ahmad Fawzi
authors.initials: AF
authors.lastname: Hussain
mesh_terms: D045744:Cell Line, Tumor; D002470:Cell Survival / Q000187:drug effects / Q000528:radiation effects; D011508:Chondroitin Sulfate Proteoglycans / Q000276:immunology / Q000378:metabolism; D000071858:Epithelial Cell Adhesion Molecule / Q000276:immunology / Q000378:metabolism; D066246:ErbB Receptors / Q000276:immunology / Q000378:metabolism; D005260:Female; D006147:Guanine / Q000031:analogs & derivatives / Q000737:chemistry; D006801:Humans; D018796:Immunoconjugates / Q000737:chemistry / Q000627:therapeutic use*; D007211:Indoles / Q000737:chemistry / Q000627:therapeutic use*; D054833:Isoindoles; D008027:Light; D061986:MCF-7 Cells; D008565:Membrane Proteins / Q000276:immunology / Q000378:metabolism; D018613:Microscopy, Confocal; D017646:Organosilicon Compounds / Q000737:chemistry / Q000627:therapeutic use*; D010778:Photochemotherapy / Q000379:methods*; D017319:Photosensitizing Agents / Q000737:chemistry / Q000627:therapeutic use; D011993:Recombinant Fusion Proteins / Q000737:chemistry; D057127:Single-Chain Antibodies / Q000737:chemistry / Q000276:immunology; D064726:Triple Negative Breast Neoplasms / Q000175:diagnosis / Q000188:drug therapy* / Q000378:metabolism; D000099216:Chondroitin Sulfate Proteoglycan 4
chemical_list: D011508:Chondroitin Sulfate Proteoglycans; D000071858:Epithelial Cell Adhesion Molecule; D066246:ErbB Receptors; D006147:Guanine; D018796:Immunoconjugates; D007211:Indoles; D054833:Isoindoles; D008565:Membrane Proteins; D017646:Organosilicon Compounds; D017319:Photosensitizing Agents; D011993:Recombinant Fusion Proteins; D057127:Single-Chain Antibodies; C101390:CSPG4 protein, human; D000099216:Chondroitin Sulfate Proteoglycan 4; C000623382:IRDye700DX N-hydroxysuccinimide ester; C064976:O(6)-benzylguanine; C013647:phthalocyanine
keywords: antibody-based therapy; breast cancer; molecular targeting; photodynamic therapy; theranostics