SIRPα-antibody fusion proteins stimulate phagocytosis and promote elimination of acute myeloid leukemia cells
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Laia Pascual Ponce1,5, Nadja C. Fenn1, Nadine Moritz1, Christina Krupka2,3, Jan-Hendrik Kozik1, Kirsten Lauber4, Marion Subklewe2,3, Karl-Peter Hopfner1,5
1Gene Center Munich, Department of Biochemistry, Ludwig-Maximilians-Universität München, Munich, Germany
2Department of Internal Medicine III, Klinikum der Universität München, Ludwig-Maximilians-Universität München, Munich, Germany
3Gene Center and Clinical Co-operation Group Immunotherapy at the Helmholtz Zentrum München, Munich, Germany
4Department of Radiation Oncology, Klinikum der Universität München, Ludwig-Maximilians-Universität München, Munich, Germany
5Graduate School of Quantitative Biosciences Munich, Ludwig-Maximilians-Universität München, Munich, Germany
Karl-Peter Hopfner, email: [email protected]
Keywords: therapeutic antibody, immunotherapy, CD47, SIRPα, acute myeloid leukemia
Received: August 02, 2016 Accepted: December 12, 2016 Published: January 04, 2017
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.
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