SIRP alpha-antibody fusion proteins stimulate phagocytosis and promote elimination of acute myeloid leukemia cells

Ponce, Laia Pascual; Fenn, Nadja C.; Moritz, Nadine; Krupka, Christina; Kozik, Jan-Hendrik; Lauber, Kirsten; Subklewe, Marion und Hopfner, Karl-Peter (2017): SIRP alpha-antibody fusion proteins stimulate phagocytosis and promote elimination of acute myeloid leukemia cells. In: Oncotarget, Bd. 8, Nr. 7: S. 11284-11301

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 SIRP alpha. Recent studies have shown that blocking the CD47-SIRP alpha 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-SIRP alpha signaling pathway at the tumor site, we developed a so-called local inhibitory checkpoint monoclonal antibody (licMAB) by grafting the endogenous SIRP alpha 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-SIRP alpha axis to tumor antigen-expressing cells.

• Dokumententyp: Zeitschriftenartikel
• Fakultät: Medizin ; Chemie und Pharmazie > Department Biochemie
• Themengebiete: 600 Technik, Medizin, angewandte Wissenschaften > 610 Medizin und Gesundheit ; 500 Naturwissenschaften und Mathematik > 540 Chemie
• ISSN: 1949-2553
• Sprache: Englisch