Catalyseurs supportés pour la conversion des liquéfiats de charbon.

nationa

Catalyseurs supportés pour la conversion des liquéfiats de charbon.

nationa

Detailed characterization of caol-derived liquids from direct coal liquefaction on supported catalysts.

internationa

Coal-derived liquid asphaltenes diffusion and adsorption in supported hydrotreating catalysts

RAFFINAGE+LRO:JST:CGE:MTFHindered diffusion and adsorption phenomena of coal asphaltenes inside the porous network of hydrotreating catalysts are discussed in this paper. After solvent extraction from a coal-derived liquid and solubilization in THF, asphaltenes were contacted with a series of mesoporous hydrotreating catalysts and adsorption-diffusion phenomena recorded by UV-Vis spectroscopy measurements. The effect of the porosity of various NiMo(P) catalysts supported on monomodal mesoporous or bimodal (meso-macro) alumina carrier was investigated. The parameters estimations have been performed, discussed and those obtained with the bimodal (meso-macro) alumina catalyst have been compared to petroleum asphaltenes data [31]. The range of studied concentrations corresponds to cluster formation domain. The results evidence that coal asphaltenes aggregates are smaller, have lower molecular weight and exhibit a much higher diffusion coefficient than petroleum asphaltene aggregates. These results bring important insights for the interpretation of the performance of the catalysts during coal-derived liquid upgrading. Concerning adsorption phenomena, the adsorption constants of coal asphaltenes and petroleum asphaltenes have been found equivalent. The adsorption saturation concentration of coal asphaltenes is higher than that of petroleum asphaltenes. The effective diffusion coefficients obtained at ambient temperature were correlated to the catalytic performances observed during coal-derived liquid hydrotreatment. It points out that the conversion of coal-derived liquid into the porous network of our catalyst is a hindered phenomenon, and that pore size distribution of the support has a great influence on the hydroliquefaction efficiency. (C) 2013 Elsevier Ltd. All rights reserved

Detailed characterization of coal-derived liquids from direct coal liquefaction on supported catalysts

RAFFINAGE+JST:CLO:CGECoal liquids from Direct Coal Liquefaction (DCL) are one of the possible substitutes of conventional hydrocarbons resources. However the primary liquids obtained from DCL (i.e. outflow liquids of the first reactor in a two stages liquefaction process) do not meet the product specifications and need to be upgraded via downstream catalytic hydrotreatment processes. The in depth knowledge of the feed of this upgrading step is of key importance to design better catalysts. In this study, we applied new cutting-edge techniques to improve the characterization of a coal derived liquid obtained from a liquefaction step starting from Scottish bituminous coal. For this purpose, bidimensional chromatography (GC xGC), and C-13 nuclear magnetic resonance (NMR) were used to analyze four cuts of the coal liquid with the following boiling points intervals: heavy naphtha (initial boiling point: IBP-215 degrees C), gas oil (215-343 degrees C), vacuum gas oil (343-524 degrees C) and vacuum residue (524(+) degrees C). The analyses showed high aromaticity of all four cuts. The weight content of aromatics in the gas oil fraction, was 75%, with a majority of two rings aromatics and the remainder consisting mostly of normal paraffins. In the vacuum gas oil cut, which contains mostly four aromatic rings, we found 11 wt% of asphaltenes (compounds in n-heptane), an unexpected high amount comparing to petroleum VGO fractions. The amount of heptane-insoluble (asphaltenes, pre-asphaltenes and sediments) is as high as 80% in the vacuum residue fraction (524(+) degrees C). Aromaticity given by C-13 NMR in this cut is as high as the level observed in petroleum asphaltenes (C-aro = 53 wt%). High content of heteroelements, which highly increase the polarity of the molecules, in the coal liquid and especially in the vacuum residue can explain the enhanced amount of n-heptane-insoluble compounds. (C) 2011 Elsevier Ltd. All rights reserved

Unique carbohydrate–carbohydrate interactions are required for high affinity binding between FcγRIII and antibodies lacking core fucose

Antibody-mediated cellular cytotoxicity (ADCC), a key immune effector mechanism, relies on the binding of antigen–antibody complexes to Fcγ receptors expressed on immune cells. Antibodies lacking core fucosylation show a large increase in affinity for FcγRIIIa leading to an improved receptor-mediated effector function. Although afucosylated IgGs exist naturally, a next generation of recombinant therapeutic, glycoenginereed antibodies is currently being developed to exploit this finding. In this study, the crystal structures of a glycosylated Fcγ receptor complexed with either afucosylated or fucosylated Fc were determined allowing a detailed, molecular understanding of the regulatory role of Fc-oligosaccharide core fucosylation in improving ADCC. The structures reveal a unique type of interface consisting of carbohydrate–carbohydrate interactions between glycans of the receptor and the afucosylated Fc. In contrast, in the complex structure with fucosylated Fc, these contacts are weakened or nonexistent, explaining the decreased affinity for the receptor. These findings allow us to understand the higher efficacy of therapeutic antibodies lacking the core fucose and also suggest a unique mechanism by which the immune system can regulate antibody-mediated effector functions

Cergutuzumab amunaleukin (CEA-IL2v), a CEA-targeted IL-2 variant-based immunocytokine for combination cancer immunotherapy: Overcoming limitations of aldesleukin and conventional IL-2-based immunocytokines

We developed cergutuzumab amunaleukin (CEA-IL2v, RG7813), a novel monomeric CEA-targeted immunocytokine, that comprises a single IL-2 variant (IL2v) moiety with abolished CD25 binding, fused to the C-terminus of a high affinity, bivalent carcinoembryonic antigen (CEA)-specific antibody devoid of Fc-mediated effector functions. Its molecular design aims to (i) avoid preferential activation of regulatory T-cells vs. immune effector cells by removing CD25 binding; (ii) increase the therapeutic index of IL-2 therapy by (a) preferential retention at the tumor by having a lower dissociation rate from CEA-expressing cancer cells vs. IL-2R-expressing cells, (b) avoiding any FcγR-binding and Fc effector functions and (c) reduced binding to endothelial cells expressing CD25; and (iii) improve the pharmacokinetics, and thus convenience of administration, of IL-2. The crystal structure of the IL2v-IL-2Rβγ complex was determined and CEA-IL2v activity was assessed using human immune effector cells. Tumor targeting was investigated in tumor-bearing mice using 89Zr-labeled CEA-IL2v. Efficacy studies were performed in (a) syngeneic mouse models as monotherapy and combined with anti-PD-L1, and in (b) xenograft mouse models in combination with ADCC-mediating antibodies. CEA-IL2v binds to CEA with pM avidity but not to CD25, and consequently did not preferentially activate Tregs. In vivo, CEA-IL2v demonstrated superior pharmacokinetics and tumor targeting compared with a wild-type IL-2-based CEA immunocytokine (CEA-IL2wt). CEA-IL2v strongly expanded NK and CD8+ T cells, skewing the CD8+:CD4+ ratio toward CD8+ T cells both in the periphery and in the tumor, and mediated single agent efficacy in syngeneic MC38-CEA and PancO2-CEA models. Combination with trastuzumab, cetuximab and imgatuzumab, all of human IgG1 isotype, resulted in superior efficacy compared with the monotherapies alone. Combined with anti-PD-L1, CEA-IL2v mediated superior efficacy over the respective monotherapies, and over the combination with an untargeted control immunocytokine. These preclinical data support the ongoing clinical investigation of the cergutuzumab amunaleukin immunocytokine with abolished CD25 binding for the treatment of CEA-positive solid tumors in combination with PD-L1 checkpoint blockade and ADCC competent antibodies

DNA-Encoded Library-Derived DDR1 Inhibitor Prevents Fibrosis and Renal Function Loss in a Genetic Mouse Model of Alport Syndrome

The importance of Discoidin Domain Receptor 1 (DDR1) in renal fibrosis has been shown via gene knockout and use of antisense oligonucleotides; however, these techniques act via a reduction of DDR1 protein, while we prove the therapeutic potential of inhibiting DDR1 phosphorylation with a small molecule. To date, efforts to generate a selective small-molecule to specifically modulate the activity of DDR1 in an in vivo model have been unsuccessful. We performed parallel DNA encoded library screens against DDR1 and DDR2, and discovered a chemical series that is highly selective for DDR1 over DDR2. Structure-guided optimization efforts yielded the potent DDR1 inhibitor 2.45, which possesses excellent kinome selectivity (including 64-fold selectivity over DDR2 in a biochemical assay), a clean in vitro safety profile, and favorable pharmacokinetic and physicochemical properties. As desired, compound 2.45 modulates DDR1 phosphorylation in vitro as well as prevents collagen-induced activation of renal epithelial cells expressing DDR1. Compound 2.45 preserves renal function and reduces tissue damage in Col4a3-/- mice (the preclinical mouse model of Alport syndrome) when employing a therapeutic dosing regime, indicating the real therapeutic value of selectively inhibiting DDR1 phosphorylation in vivo. Our results may have wider significance as Col4a3-/- mice also represent a model for chronic kidney disease, a disease which affects 10% of the global population