[Translation] An open, multicenter, first-in-human, dose-escalation and expansion phase I clinical study to evaluate the safety, tolerability and pharmacokinetic characteristics of DXC007 (recombinant humanized anti-CD33 monoclonal antibody-Tub255 conjugate) for injection in patients with relapsed/refractory acute myeloid leukemia

评估注射用DXC007在复发/难治性急性髓系白血病患者中的安全性、耐受性、药代动力学特征。

[Translation]

To evaluate the safety, tolerability, and pharmacokinetic characteristics of DXC007 for injection in patients with relapsed/refractory acute myeloid leukemia.

Start Date30 Jun 2022

Sponsor / Collaborator

Hangzhou DAC Biotechnology Co., Ltd.

NCT00543972 / TerminatedPhase 1

An Open Label, Dose-Escalation Safety and Pharmacokinetic Study of AVE9633 Administered as a Single Agent by Intravenous Infusion on Day 1, Day 4 and Day 7 of a 4-Week Cycle in Patients With Relapsed or Refractory CD33-Positive Acute Myeloid Leukemia (AML)

The primary objective is to determine the maximum tolerated dose of AVE9633 and to characterize the dose limiting toxicity(ies). Secondary objectives are to determine the anti-leukemia activity, the global safety and the PK profile.

Start Date01 Sep 2007

Sponsor / Collaborator

Sanofi

100 Clinical Results associated with CD33 x Tubulin

100 Translational Medicine associated with CD33 x Tubulin

0 Patents (Medical) associated with CD33 x Tubulin

Literatures (Medical) associated with CD33 x Tubulin

01 Oct 2024·International Immunopharmacology

The effects of immunomodulatory drugs on cerebral small vessel disease: A mediation Mendelian randomization analysis

Article

Author: Lv, Yanchen

BACKGROUNDThere are only a few recognized drug targets for cerebral small vessel disease (CSVD). Though inflammation is increasingly implicated in the development of CSVD, it remains unclear whether immunomodulation could become a therapeutic target. Accordingly, the Mendelian randomization (MR) method was used to assess the genetically proxied impacts of IL6 receptor (IL6R) inhibitor, IL1β inhibitor, Tumor necrosis factor (TNF) inhibitor and β-tubulin inhibitor on CSVD through.METHODSSingle nucleotide polymorphisms (SNPs) near the IL6R, IL1β, TNFRSF1A and β-tubulin genes were identified as genetic proxies for immunomodulatory drugs. These SNPs exhibited significant associations with serum C-reactive protein (CRP) levels in a large European genome-wide association study. The causal effects of immunomodulatory drugs on CSVD manifestations and the mediation influence of 731 peripheral blood immune phenotypes linking these drugs to CSVD manifestations were examined using a two-sample two-step MR approach.RESULTSA total of 9, 18, 4 and 1 SNP were identified to proxy the effects of IL1β inhibitor, IL6R inhibitor, TNF inhibitor and β-tubulin inhibitor, respectively. MR analysis showed a significant causal relationship between IL1β inhibition and reduced volume of periventricular white matter hyperintensity (PWMH). IL6R inhibition was associated with a reduced risk of small vessel stroke, decreased axial diffusivity and mean diffusivity. Genetically proxied TNF inhibition may decrease the occurrence of cerebral microbleeds (CMBs) and severe enlarged perivascular spaces located at white matter (WM-EPVS). It could also protect WM integrity, as evidenced by the reduced volumes of PWMH and deep white matter hyperintensity (DWMH). Various peripheral blood immune phenotypes exhibited significant associations with immunomodulatory drugs. Notably, the median fluorescence intensity (MFI) of CD45 on CD8^br cells partially mediated the effects of IL1β inhibitor on PWMH volume. Indirect effects of TNF inhibition on PWMH and DWMH volume through the MFI of CD127 on CD28- CD8^br cells were observed. The effects of TNF inhibition on the occurrence of any CMBs were partially mediated by the MFI of CD45 on natural killer T cells, and the effects of TNF inhibition on the occurrence of lobar CMBs were partially mediated by the MFI of HLA DR on CD33- HLA DR+ cells. Furthermore, the MFI of HLA DR on CD33- HLA DR+ cells partially mediated the effects of TNF inhibition on WM-EPVS.CONCLUSIONSIL1β inhibitor, IL6R inhibitor and TNF inhibitor were associated with lower burden of CSVD while the activation of certain immune cells such as Tregs and myeloid cells partially mediated their protective effects.

01 Jul 2016·The American Journal of Human GeneticsQ1 · BIOLOGY

Large-Scale Exome-wide Association Analysis Identifies Loci for White Blood Cell Traits and Pleiotropy with Immune-Mediated Diseases

Q1 · BIOLOGY

Article

Author: Becker, Lewis C ; Liewald, David C M ; Johnson, Andrew D ; Gudnason, Vilmundur ; Pazoki, Raha ; Crosslin, David R ; Uitterlinden, Andre ; Mihailov, Evelin ; Hirschhorn, Joel N ; Burt, Amber ; Eicher, John D ; Lettre, Guillaume ; Ganesh, Santhi K ; O'Donnell, Chris J ; Hofman, Albert ; Launer, Lenore J ; Mathias, Rasika A ; Reiner, Alex P ; Brody, Jennifer A ; Greinacher, Andreas ; Li, Jin ; Boerwinkle, Eric ; Torstenson, Eric S ; Faraday, Nauder ; Lyytikäinen, Leo-Pekka ; Bartz, Traci M ; de Denus, Simon ; Dörr, Marcus ; Loos, Ruth J F ; Yanek, Lisa R ; Lu, Yingchang ; Zonderman, Alan B ; Dehghan, Abbas ; Pankratz, Nathan ; Highland, Heather M ; Vergnaud, Anne-Claire ; Auer, Paul L ; Tzoulaki, Ioanna ; Slater, Andrew J ; Psaty, Bruce M ; Hayward, Caroline ; Wallentin, Lars ; Esko, Tõnu ; Wilson, James G ; O'Donoghue, Michelle L ; Rotter, Jerome I ; Friedrich, Nele ; Fornage, Myriam ; Becker, Diane M ; Vacchi-Suzzi, Caterina ; Evans, Michele K ; Nikus, Kjell ; Velez Edwards, Digna R ; Zakai, Neil A ; Floyd, James S ; Schurmann, Claudia ; Bastarache, Lisa ; Taylor, Kent D ; Gao, He ; Mägi, Reedik ; Richard, Melissa ; Tardif, Jean-Claude ; Metspalu, Andres ; Hill, W David ; Bottinger, Erwin P ; Raffield, Laura M ; Lange, Leslie A ; Chen, Ming-Huei ; Lehtimäki, Terho ; Waterworth, Dawn M ; Denny, Joshua C ; Rioux, John D ; Kacprowski, Tim ; White, Harvey D ; Schick, Ursula M ; Starr, John M ; Edwards, Todd L ; Kähönen, Mika ; Chami, Nathalie ; Nickerson, Deborah A ; Quarells, Rakale C ; Cushman, Mary ; Tajuddin, Salman M ; Giri, Ayush ; van Rooij, Frank J A ; Manichaikul, Ani ; Smith, Albert Vernon ; Nalls, Mike A ; Lange, Ethan ; Rich, Stephen S ; Homuth, Georg ; Liu, Yongmei ; Elliott, Paul ; Evangelou, Evangelos ; Deary, Ian J ; Polfus, Linda M ; Harris, Tamara B

White blood cells play diverse roles in innate and adaptive immunity. Genetic association analyses of phenotypic variation in circulating white blood cell (WBC) counts from large samples of otherwise healthy individuals can provide insights into genes and biologic pathways involved in production, differentiation, or clearance of particular WBC lineages (myeloid, lymphoid) and also potentially inform the genetic basis of autoimmune, allergic, and blood diseases. We performed an exome array-based meta-analysis of total WBC and subtype counts (neutrophils, monocytes, lymphocytes, basophils, and eosinophils) in a multi-ancestry discovery and replication sample of ∼157,622 individuals from 25 studies. We identified 16 common variants (8 of which were coding variants) associated with one or more WBC traits, the majority of which are pleiotropically associated with autoimmune diseases. Based on functional annotation, these loci included genes encoding surface markers of myeloid, lymphoid, or hematopoietic stem cell differentiation (CD69, CD33, CD87), transcription factors regulating lineage specification during hematopoiesis (ASXL1, IRF8, IKZF1, JMJD1C, ETS2-PSMG1), and molecules involved in neutrophil clearance/apoptosis (C10orf54, LTA), adhesion (TNXB), or centrosome and microtubule structure/function (KIF9, TUBD1). Together with recent reports of somatic ASXL1 mutations among individuals with idiopathic cytopenias or clonal hematopoiesis of undetermined significance, the identification of a common regulatory 3' UTR variant of ASXL1 suggests that both germline and somatic ASXL1 mutations contribute to lower blood counts in otherwise asymptomatic individuals. These association results shed light on genetic mechanisms that regulate circulating WBC counts and suggest a prominent shared genetic architecture with inflammatory and autoimmune diseases.

01 Jan 2007·International Journal of HematologyQ4 · MEDICINE

Induction of Multilineage Markers in Human Myeloma Cells and Their Down-Regulation by Interleukin 6

Q4 · MEDICINE

Article

Author: Jakia Amin ; Zi Ma ; Michio M. Kawano ; Hideki Asaoku ; Shangqin Liu ; Karim Shamsasenjan ; Ken-ichiro Otsuyama ; Saeid Abroun

Human primary myeloma cells are well known to be heterogeneous with regard to morphology and surface phenotype. We confirmed the heterogeneous expression of such multilineage markers as CD33, CD7, CD56, CD4, and CD86 in primary myeloma cells from 20 patients with multiple myeloma and in 8 human myeloma cell lines. CD33 expression in the Liu01 cell line, a subclone of U266 cells, and in vitamin D3-treated ILKM3 cells, correlated with a monocytoid morphology featuring convoluted nuclei and with increased C/EBPalpha expression. CD56+ myeloma cells from some myeloma patients and the CD56+ (but not the CD56-) myeloma cell lines expressed neuronal cell markers, such as neuron-specific enolase and beta-tubulin III. CD7 expression in Liu01 cells and forskolin-stimulated U266 cells coincided with the presence of large cytoplasmic granules, and these cells featured increased expression of perforin messenger RNA and significant natural killer cell activity. Interleukin 6 (IL-6), a growth factor for myeloma cells, down-regulated CD33, CD7, or CD56 expression in primary myeloma cells, as well as in Liu01 cells. Therefore, these data suggest that human myeloma cells are capable of inducing the expression of multilineage markers and that IL-6 can down-regulate such expression.

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