title: Fully human MAP-fusion protein selectively targets and eliminates proliferating CD64(+) M1 macrophages.
abstract: Classical immunotoxins compromise a binding component (for example, a ligand, antibody or fragment thereof) and a cytotoxic component, usually derived from bacteria or plants (for example, Pseudomonas exotoxin A or ricin). Despite successful testing in vitro, the clinical development of immunotoxins has been hampered by immunogenicity and unsatisfactory safety profiles. Therefore, research has focused on fully human pro-apoptotic components suitable for the development of cytolytic fusion proteins (CFP). We recently reported that human microtubule-associated protein tau (MAP) can induce apoptosis when delivered to rapidly proliferating cancer cells. Here, we describe a new fully human CFP called H22(scFv)-MAP, which specifically targets CD64(+) cells. We show that H22(scFv)-MAP can efficiently kill proliferating HL-60 pro-monocytic cells in vitro. In addition, the human CFP specifically eliminates polarized M1 macrophages in a transgenic mouse model of cutaneous chronic inflammation. Because M1 macrophages promote the pathogenesis of many chronic inflammatory diseases, targeting this cell population with H22(scFv)-MAP could help to treat diseases such as atopic dermatitis, rheumatoid arthritis and inflammatory bowel disease.
authors.affiliation: Department of Experimental Medicine and Immunotherapy, Institute of Applied Medical Engineering, University Hospital, RWTH Aachen University, Aachen, Germany.
authors.forename: Dmitrij
authors.initials: D
authors.lastname: Hristodorov
authors.affiliation: Department of Experimental Medicine and Immunotherapy, Institute of Applied Medical Engineering, University Hospital, RWTH Aachen University, Aachen, Germany.
authors.forename: Radoslav
authors.initials: R
authors.lastname: Mladenov
authors.affiliation: Pharmaceutical Product Development, Fraunhofer Institute for Molecular Biology and Applied Ecology (IME), Aachen, Germany.|Institute of Molecular Biotechnology (Biology VII), RWTH Aachen University, Aachen, Germany.
authors.forename: Rainer
authors.initials: R
authors.lastname: Fischer
authors.affiliation: Department of Experimental Medicine and Immunotherapy, Institute of Applied Medical Engineering, University Hospital, RWTH Aachen University, Aachen, Germany.|Pharmaceutical Product Development, Fraunhofer Institute for Molecular Biology and Applied Ecology (IME), Aachen, Germany.
authors.forename: Stefan
authors.initials: S
authors.lastname: Barth
authors.affiliation: Pharmaceutical Product Development, Fraunhofer Institute for Molecular Biology and Applied Ecology (IME), Aachen, Germany.
authors.forename: Theo
authors.initials: T
authors.lastname: Thepen
mesh_terms: D000818:Animals; D017209:Apoptosis / Q000187:drug effects; D002460:Cell Line; D016764:Cell Polarity / Q000187:drug effects; D049109:Cell Proliferation / Q000187:drug effects; D002478:Cells, Cultured; D002908:Chronic Disease; D006801:Humans; D007249:Inflammation / Q000473:pathology; D007371:Interferon-gamma / Q000494:pharmacology; D008264:Macrophages / Q000166:cytology* / Q000187:drug effects / Q000378:metabolism*; D051379:Mice; D008870:Microtubules / Q000187:drug effects / Q000378:metabolism; D011485:Protein Binding / Q000187:drug effects; D017452:Receptors, IgG / Q000378:metabolism*; D011993:Recombinant Fusion Proteins / Q000494:pharmacology*; D057127:Single-Chain Antibodies / Q000378:metabolism; D012867:Skin / Q000473:pathology; D016875:tau Proteins / Q000494:pharmacology*
chemical_list: C054369:MAPT protein, human; D017452:Receptors, IgG; D011993:Recombinant Fusion Proteins; D057127:Single-Chain Antibodies; D016875:tau Proteins; D007371:Interferon-gamma