Novel therapeutic approach to improve hematopoiesis in low risk MDS by targeting MDSCs with the Fc-engineered CD33 antibody BI 836858.

We recently reported that the accumulation of myeloid-derived suppressor cells (MDSC), defined as CD33+HLA-DR-Lin-, has a direct role in the pathogenesis of myelodysplastic syndrome (MDS). In particular, CD33 is strongly expressed in MDSC isolated from patients with MDS where it has an important role in MDSC-mediated hematopoietic suppressive function through its activation by S100A9. Therefore, we tested whether blocking this interaction with a fully human, Fc-engineered monoclonal antibody against CD33 (BI 836858) suppresses CD33-mediated signal transduction and improves the bone marrow microenvironment in MDS. We observed that BI 836858 can reduce MDSC by antibody-dependent cellular cytotoxicity, which correlated with increases in granule mobilization and cell death. BI 836858 can also block CD33 downstream signaling preventing immune-suppressive cytokine secretion, which correlates with a significant increase in the formation of CFU-GM and BFU-E colonies. Activation of the CD33 pathway can cause reactive oxygen species (ROS)-induced genomic instability but BI 836858 reduced both ROS and the levels of double strand breaks and adducts (measured by comet assay and γH2AX). This work provides the ground for the development of a novel group of therapies for MDS aimed at MDSC and their disease-promoting properties with the goal of improving hematopoiesis in patients.

Purinergic regulation of ion transport across nonciliated bronchiolar epithelial (Clara) cells.

Previous studies demonstrated that elevation of intracellular calcium concentration ([Ca2+]i) increased electrogenic anion transport by bronchiolar epithelia. Extracellular nucleotides were shown to elevate [Ca2+]i and transepithelial short-circuit current (Isc) in proximal airways epithelia. In this study purine and pyrimidine nucleotides were investigated for their ability to regulate ion transport by rabbit nonciliated bronchiolar epithelial (Clara) cells in culture. ATP in the apical bath induced a concentration-dependent transient increase in [Ca2+]i and Isc. Mean effective doses (ED50) of the responses were 10(-7) M and 10(-6) M, respectively. Transepithelial resistance (Rt) decreased. The peak changes in Isc and Rt were 7.8 +/- 1.2 microA/cm2 and -59 +/- 14 omega.cm2 (n = 26, basal Isc = 47.4 +/- 4.3 microA/cm2 and Rt = 428 +/- 40 omega.cm2). Some preparations exhibited a small residual increase in Isc after the initial response, but the change was not statistically significant (delta Isc = 1.7 +/- 1.2 microA/cm2, n = 18). Addition of ATP to the basolateral bath had no detectable effects. Purinoceptor agonists were used to characterize the receptors mediating the change in Isc. UTP and ATP gamma S increased Isc and inhibited subsequent stimulation by ATP. ADP, ADP beta S, 2-methylthio-ATP, and alpha, beta-methylene-ATP had negligible effects on the peak delta Isc and subsequent stimulation by ATP. The ionic mechanism underlying the ATP-induced increase in Isc was investigated with the use of specific ion-transport inhibitors and by ion substitution.(ABSTRACT TRUNCATED AT 250 WORDS)