PuSH - Publikationsserver des Helmholtz Zentrums München

Ponce, L.P.* ; Fenn, N.C.* ; Moritz, N.* ; Krupka, C. ; Kozik, J.H.* ; Lauber, K.* ; Subklewe, M. ; Hopfner, K.P.*

SIRPα-antibody fusion proteins stimulate phagocytosis and promote elimination of acute myeloid leukemia cells.

Oncotarget 8, 11284-11301 (2017)
Verlagsversion Forschungsdaten DOI
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.
Altmetric
Weitere Metriken?
[➜Einloggen]
Zusatzinfos bearbeiten [➜Einloggen]
Publikationstyp Artikel: Journalartikel
Dokumenttyp Wissenschaftlicher Artikel
Korrespondenzautor
Schlagwörter Acute Myeloid Leukemia ; Cd47 ; Immunotherapy ; Sirpα ; Therapeutic Antibody; Acute Myelogenous Leukemia; Gemtuzumab Ozogamicin; Amg 330; Stem-cells; Cancer-immunotherapy; Therapeutic Target; Engaging Antibody; Flow-cytometry; Bite Antibody; Cd47
ISSN (print) / ISBN 1949-2553
e-ISSN 1949-2553
Zeitschrift OncoTarget
Quellenangaben Band: 8, Heft: 7, Seiten: 11284-11301 Artikelnummer: , Supplement: ,
Verlag Impact Journals LLC
Verlagsort Orchard Park
Nichtpatentliteratur Publikationen
Begutachtungsstatus Peer reviewed
Institut(e) CCG Immunotherapy (KKG-KIT)