Preclinical efficacy of daratumumab in T-cell acute lymphoblastic leukemia (T-ALL).

2018

995-9

2018 Mar

1528-0020

<p>As a consequence of acquired or intrinsic disease resistance, the prognosis for patients with relapsed or refractory T-cell acute lymphoblastic leukemia (T-ALL) is dismal. Novel, less toxic drugs are clearly needed. One of the most promising emerging therapeutic strategies for cancer treatment is targeted immunotherapy. Immune therapies have improved outcomes for patients with other hematologic malignancies including B-ALL, however no immune therapy has been successfully developed for T-ALL. We hypothesize targeting CD38 will be effective against T-ALL. We demonstrate that blasts from patients with T-ALL have robust surface CD38 surface expression and that this expression remains stable after exposure to multi-agent chemotherapy. CD38 is expressed at very low levels on normal lymphoid and myeloid cells and on a few tissues of non-hematopoietic origin, suggesting that CD38 may be an ideal target. Daratumumab is a human IgG1κ monoclonal antibody that binds CD38, and has been demonstrated to be safe and effective in patients with refractory multiple myeloma (MM). We tested daratumumab in a large panel of T-ALL patient-derived xenografts (PDX) and found striking efficacy in 14 of 15 different PDX. These data suggest that daratumumab is a promising novel therapy for pediatric T-ALL patients.</p>

10.1182/blood-2017-07-794214

Blood

29305553

Improved plasma membrane proteome coverage with a label-free non-affinity-purified workflow.

2017

2017 Jan 23

1615-9861

<p>The proteins of the cellular plasma membrane perform important functions relating to homeostasis and intercellular communication. Due to its overall low cellular abundance, amphipathic character, and low membrane-to-cytoplasm ratio, the plasma membrane proteome has been challenging to isolate and characterize, and is poorly represented in standard liquid chromatography-tandem mass spectrometry (LC-MS/MS) analyses. In this study, we employ sucrose gradient ultracentrifugation for the enrichment of the plasma membrane proteome, without chemical labeling and affinity purification, together with GeLCMS and use subsequent bioinformatics tools to select plasma membrane proteins, herein referred to as the surfaceome. Using this methodology, we identify over 1900 cell surface-associated proteins in a human acute myeloid leukemia (AML) cell line. These surface proteins comprise almost 50% of all detected cellular proteins, a number that substantially exceeds the depth of coverage in previously published studies describing the leukemia surfaceome. This article is protected by copyright. All rights reserved.</p>

10.1002/pmic.201600344

Proteomics

28116781