title: SIRPα-antibody fusion proteins stimulate phagocytosis and promote elimination of acute myeloid leukemia cells.
abstract: CD47, expressed on a variety of tumor cells, confers immune resistance by delivering an inhibitory "don't eat me" signal to phagocytic cells via its myeloid-specific receptor SIRPα. Recent studies have shown that blocking the CD47-SIRPα axis with CD47-directed antibodies or antibody-derivatives enhances phagocytosis and increases antitumor immune effects. However, CD47 expression on healthy cells creates an antigen sink and potential sites of toxicity, limiting the efficacy of CD47-directed therapies. In this study, we first characterized CD47 expression in Acute Myeloid Leukemia (AML) patients (n = 213) and found that CD47 is highly expressed on both AML bulk and stem cells irrespective of the disease state. Furthermore, to inhibit the CD47-SIRPα signaling pathway at the tumor site, we developed a so-called local inhibitory checkpoint monoclonal antibody (licMAB) by grafting the endogenous SIRPα domain to the N-terminus of the light chain of an antibody targeting CD33, a surface antigen expressed in AML. LicMABs selectively bind CD33-expressing cells even in the presence of a large CD33-negative CD47-positive antigen sink, stimulate phagocytosis of AML cells and eliminate AML cell lines and primary, patient-derived AML cells. Our findings qualify licMABs as a promising therapeutic approach to confine the benefit of disrupting the CD47-SIRPα axis to tumor antigen-expressing cells.
authors.affiliation: Gene Center Munich, Department of Biochemistry, Ludwig-Maximilians-Universität München, Munich, Germany.|Graduate School of Quantitative Biosciences Munich, Ludwig-Maximilians-Universität München, Munich, Germany.
authors.forename: Laia Pascual
authors.initials: LP
authors.lastname: Ponce
authors.affiliation: Gene Center Munich, Department of Biochemistry, Ludwig-Maximilians-Universität München, Munich, Germany.
authors.forename: Nadja C
authors.initials: NC
authors.lastname: Fenn
authors.affiliation: Gene Center Munich, Department of Biochemistry, Ludwig-Maximilians-Universität München, Munich, Germany.
authors.forename: Nadine
authors.initials: N
authors.lastname: Moritz
authors.affiliation: Department of Internal Medicine III, Klinikum der Universität München, Ludwig-Maximilians-Universität München, Munich, Germany.|Gene Center and Clinical Co-operation Group Immunotherapy at the Helmholtz Zentrum München, Munich, Germany.
authors.forename: Christina
authors.initials: C
authors.lastname: Krupka
authors.affiliation: Gene Center Munich, Department of Biochemistry, Ludwig-Maximilians-Universität München, Munich, Germany.
authors.forename: Jan-Hendrik
authors.initials: JH
authors.lastname: Kozik
authors.affiliation: Department of Radiation Oncology, Klinikum der Universität München, Ludwig-Maximilians-Universität München, Munich, Germany.
authors.forename: Kirsten
authors.initials: K
authors.lastname: Lauber
authors.affiliation: Department of Internal Medicine III, Klinikum der Universität München, Ludwig-Maximilians-Universität München, Munich, Germany.|Gene Center and Clinical Co-operation Group Immunotherapy at the Helmholtz Zentrum München, Munich, Germany.
authors.forename: Marion
authors.initials: M
authors.lastname: Subklewe
authors.affiliation: Gene Center Munich, Department of Biochemistry, Ludwig-Maximilians-Universität München, Munich, Germany.|Graduate School of Quantitative Biosciences Munich, Ludwig-Maximilians-Universität München, Munich, Germany.
authors.forename: Karl-Peter
authors.initials: KP
authors.lastname: Hopfner
mesh_terms: D019138:Antibodies, Blocking / Q000494:pharmacology*; D000911:Antibodies, Monoclonal / Q000494:pharmacology; D000920:Antibody-Dependent Cell Cytotoxicity / Q000276:immunology; D000943:Antigens, Differentiation / Q000494:pharmacology*; D051928:CD47 Antigen / Q000096:biosynthesis / Q000276:immunology; D002469:Cell Separation; D005434:Flow Cytometry; D006801:Humans; D007167:Immunotherapy / Q000379:methods*; D015470:Leukemia, Myeloid, Acute / Q000276:immunology*; D018613:Microscopy, Confocal; D010587:Phagocytosis / Q000187:drug effects*; D011971:Receptors, Immunologic; D063268:Sialic Acid Binding Ig-like Lectin 3 / Q000276:immunology*
chemical_list: D019138:Antibodies, Blocking; D000911:Antibodies, Monoclonal; D000943:Antigens, Differentiation; C571163:CD33 protein, human; D051928:CD47 Antigen; C497894:CD47 protein, human; D011971:Receptors, Immunologic; C501920:SIRPA protein, human; D063268:Sialic Acid Binding Ig-like Lectin 3
keywords: CD47; SIRPα; acute myeloid leukemia; immunotherapy; therapeutic antibody