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Daniela Dukovska, Daniel Fernández-Soto, Mar Valés-Gómez, Hugh T Reyburn
The biology and function of NKG2H receptor, unlike the better characterized members of the NKG2 family NKG2A, NKG2C, and NKG2D, remains largely unclear. Here, we show that NKG2H is able to associate with the signaling adapter molecules DAP12 and DAP10 suggesting that this receptor can signal for cell activation. Using a recently described NKG2H-specific monoclonal antibody (mAb), we have characterized the expression and function of lymphocytes that express this receptor. NKG2H is expressed at the cell surface of a small percentage of peripheral blood mononuclear cell (PBMC) and is found more frequently on T cells, rather than NK cells...
2018: Frontiers in Immunology
Takehiro Takahashi, Yoko Koga, Mie Kainoh
Psoriasis is a chronic inflammatory skin disease characterized by erythema, skin hyperplasia, scales, and keratinocyte hyperproliferation. While the cause of psoriasis is not clearly understood, a dysregulated immune system, especially activation of IL-23/IL-17 axis, has been strongly implicated in the pathogenesis of psoriasis. For example, anti-IL-23 therapy is effective in psoriasis patients, and thus IL-23 is considered as a potential therapeutic target for the treatment of psoriasis. The skin barrier provides protection of the human body against infection from external pathogens...
March 12, 2018: European Journal of Pharmacology
Luhong He, Jairav Xolo Desai, Jinxin Gao, Laurie B Hazeltine, Zhirui Lian, John N Calley, Christopher C Frye
Oxidation of monoclonal antibodies (mAb) is a common chemical modification with potential impact on a therapeutic protein's activity and immunogenicity. In a previous study, it was found that tryptophan oxidation (Trp-ox) levels of two mAb produced in Chinese hamster ovary (CHO) cells were significantly lowered by modifying cell culture medium/feed. In this study, transcriptome analysis by RNA-Seq was applied to further elucidate the underlying mechanism of those changes in lowering the Trp-ox levels. Cell samples from the 5L fed-batch conditions were harvested and subjected to RNA-Seq analysis...
March 15, 2018: Biotechnology Journal
Sheun Oshinbolu, Rachana Shah, Gary Finka, Mike Molloy, Mark Uden, Daniel G Bracewell
BACKGROUND: A current challenge in bioprocessing is the ability to analyse critical quality attributes such as aggregation without prior purification. This study evaluated the use of fluorescent dyes (Bis-ANS, SYPRO Orange, Thioflavin T and ProteoStat) to characterise mAb aggregates in Chinese hamster ovary clarified cultures. RESULTS: The null and mAb culture supernatants showed an increase in fluorescence intensity over the duration of the culture. The null cultures on day 14 saw a rapid increase in fluorescence intensity; day 10 to day 14, Bis-ANS and Thioflavin T had average increases of 21% and 48%, respectively, whereas ProteoStat and SYPRO Orange showed an average increase of 60%...
March 2018: Journal of Chemical Technology and Biotechnology
Valeryi K Lishko, Valentin P Yakubenko, Tatiana P Ugarova, Nataly P Podolnikova
Platelet Factor 4 (PF4) is one of the most abundant cationic proteins secreted from α-granules of activated platelets. Based on its structure, PF4 was assigned to the CXC family of chemokines and has been shown to have numerous effects on myeloid leukocytes. However, the receptor for PF4 remains unknown. Here, we demonstrate that PF4 induces leukocyte responses through the integrin Mac-1 (αM β2 , CD11b/CD18). Human neutrophils, monocytes, U937 monocytic and HEK293 cells expressing Mac-1 strongly adhered to immobilized PF4 in a concentration-dependent manner...
March 14, 2018: Journal of Biological Chemistry
Mattia Laffranchi, Romina Berardelli, Riccardo Ronzoni, David A Lomas, Annamaria Fra
The most common genotype associated with severe α1-antitrypsin deficiency (AATD) is the Z homozygote. The Z variant (Glu342Lys) of α1-antitrypsin (AAT) undergoes a conformational change and is retained within the endoplasmic reticulum (ER) of hepatocytes leading to the formation of ordered polymeric chains and inclusion bodies. Accumulation of mutated protein predisposes to cirrhosis whilst plasma AAT deficiency leads to emphysema. Increased risk of liver and lung disease has also been reported in heterozygous subjects who carry Z in association with the milder S allele (Glu264Val) or even with wild-type M...
March 10, 2018: Human Molecular Genetics
Dan Boyd, Arpa Ebrahimi, Sarah Ronan, Brian Mickus, Matthew Schenauer, Jenny Wang, Darren Brown, Alexandre Ambrogelly
Isolation and characterization of monoclonal antibody (mAb) variants to understand the impact of their structure on function is a typical activity during early-stage candidate selection that contributes to derisking clinical development. In particular, efforts are devoted to characterizing oligomeric variants, owing to their potential immunogenic nature. We report here a mAb variant consisting of a canonical mAb monomer associated in a non-covalent fashion with an antigen-binding fragment (Fab) arm amputated from its Fc domain...
March 14, 2018: MAbs
Vaclav Janovec, Besma Aouar, Albert Font-Haro, Tomas Hofman, Katerina Trejbalova, Jan Weber, Laurence Chaperot, Joel Plumas, Daniel Olive, Patrice Dubreuil, Jacques A Nunès, Ruzena Stranska, Ivan Hirsch
Recent studies have reported that the crosslinking of regulatory receptors (RRs), such as blood dendritic cell antigen 2 (BDCA-2) (CD303) or ILT7 (CD85g), of plasmacytoid dendritic cells (pDCs) efficiently suppresses the production of type I interferons (IFN-I, α/β/ω) and other cytokines in response to toll-like receptor 7 and 9 (TLR7/9) ligands. The exact mechanism of how this B cell receptor (BCR)-like signaling blocks TLR7/9-mediated IFN-I production is unknown. Here, we stimulated BCR-like signaling by ligation of RRs with BDCA-2 and ILT7 mAbs, hepatitis C virus particles, or BST2 expressing cells...
2018: Frontiers in Immunology
Xiangyu Wang, Donghai Xia, Hai Han, Kun Peng, Peijie Zhu, Jacques Crommen, Qiqin Wang, Zhengjin Jiang
The rapid development of monoclonal antibodies (mAbs) in therapeutic and diagnostic applications has necessitated the advancement of mAbs purification technologies. In this study, a biomimetic small peptide ligand 3,5-di-tert-butyl-4-hydroxybenzoic acid-Arg-Arg-Gly (DAAG) functionalized monolith was fabricated through a metal ion chelation-based multi-step approach. The resulting monolith showed good chromatographic performance. Compared with the Ni2+ based IMAC monolith, the DAAG functionalized monolith exhibited not only excellent specificity but also higher dynamic binding capacity (DBC)...
August 9, 2018: Analytica Chimica Acta
E N Ilina, M V Larina, T K Aliev, D A Dolgikh, M P Kirpichnikov
Rabies virus is a prototypical neurotropic virus that causes one of the most dangerous zoonotic diseases in humans. Humanized or fully human monoclonal antibodies (mAb) that neutralize rabies virus would be the basis for powerful post-exposure prophylaxis of rabies in humans, having several significant benefits in comparison with human or equine rabies polyclonal immunoglobulins. The most advanced antibodies should broadly neutralize natural rabies virus isolates, bind with conserved antigenic determinants of the rabies virus glycoprotein, and show high neutralizing potency in assays in vivo...
January 2018: Biochemistry. Biokhimii︠a︡
Roland B Walter
There is long-standing interest in drugs targeting the myeloid differentiation antigen CD33 in acute myeloid leukemia (AML). Positive results from randomized trials with the antibody-drug conjugate (ADC) gemtuzumab ozogamicin (GO) validate this approach. Partly stimulated by the success of GO, several CD33-targeted therapeutics are currently in early phase testing. Areas covered: CD33-targeted therapeutics in clinical development include Fc-engineered unconjugated antibodies (BI 836858 [mAb 33.1]), ADCs (SGN-CD33A [vadastuximab talirine], IMGN779), radioimmunoconjugates (225 Ac-lintuzumab), bi- and trispecific antibodies (AMG 330, AMG 673, AMV564, 161533 TriKE fusion protein), and chimeric antigen receptor (CAR)-modified immune effector cells...
March 15, 2018: Expert Opinion on Investigational Drugs
Takenobu Ishii, Montserrat Ruiz-Torruella, Atsushi Ikeda, Satoru Shindo, Alexandru Movila, Hani Mawardi, Abdullah Albassam, Rayyan A Kayal, Ayman A Al-Dharrab, Kenji Egashira, Wichaya Wisitrasameewong, Kenta Yamamoto, Abdulghani I Mira, Kenji Sueishi, Xiaozhe Han, Martin A Taubman, Takeshi Miyamoto, Toshihisa Kawai
Cell fusion-mediated formation of multinuclear osteoclasts (OCs) plays a key role in bone resorption. It is reported that 2 unique OC-specific fusogens [ i.e., OC-stimulatory transmembrane protein (OC-STAMP) and dendritic cell-specific transmembrane protein (DC-STAMP)], and permissive fusogen CD9, are involved in OC fusion. Contrast to DC-STAMP of which knockout (KO) mice show osteopetrotic phenotype, OC-STAMP-KO mice show no difference in systemic bone mineral density. Nonetheless, according to the ligature-induced periodontitis model, significantly lower level of bone resorption was found in OC-STAMP-KO mice compared to WT mice...
March 13, 2018: FASEB Journal: Official Publication of the Federation of American Societies for Experimental Biology
Inna A Galvidis, Zhanhui Wang, Rinat I Nuriev, Maksim A Burkin
The recognition spectrum of immunoassays developed on the basis of class-specific antibodies can include the several nearest analytes but rarely all of the desired representatives of the group. The situation may be sufficiently improved using a hybrid assay combining two antibodies with specificities that complement each other. Two monoclonal antibodies (mAb) with broad but different specificities towards sulfonamides were examined for their binding to a panel of hapten conjugates. MAb - hapten pairs without mutual cross-reactions were identified, and classical direct antigen-coated and mAb-coated ELISAs were developed as formats with referent specificities...
March 13, 2018: Analytical Chemistry
Xiao-Zhen Kang, Xue-Ran Guo, Bin-Bing Chen, Tian-Ying Zhang, Quan Yuan, Pei-Jer Chen, Jun Zhang, Ning-Shao Xia
There are estimated 248 million individuals worldwide persistently infected with hepatitis B virus (HBV), if without timely and effective treatment, about 25%-40% of whom would develop to liver cancer, cirrhosis or other HBV related end-stage liver diseases. Our previously study has reported a unique antibody named E6F6, that recognizes HBsAg-aa119-125 and is capable of prolonged suppression of HBsAg and HBV DNA levels in mice. In this study, data revealed that the consecutive E6F6 treatments can not only effectively inhibit HBV viremia, but also significantly reduce HBV-induced hepatocarcinogenesis in DEN-treated HBV-Tg mice...
March 13, 2018: Human Vaccines & Immunotherapeutics
Cecilia Augustsson, Anders Svensson, Birgitte Kjaer, Tzu-Yuan Chao, Xia Wenjuan, Berit Olsen Krogh, Jens Breinholt, Jes Thorn Clausen, Ida Hilden, Helle Heibroch Petersen, Lars Christian Petersen
BACKGROUND: Initiation of coagulation is induced by binding of activated factor VII (FVIIa) to tissue factor (TF) and activation of factor X (FX) in a process regulated by tissue factor pathway inhibitor (TFPI). TFPI contains three Kunitz-type protease inhibitor domains (K1-K3) of which K1 and K2 block the active sites of FVIIa and FXa respectively. OBJECTIVE: To produce a monoclonal antibody (mAb) directed towards K1, to characterize the binding epitope, and to study its effect on TFPI inhibition...
March 12, 2018: Journal of Thrombosis and Haemostasis: JTH
Aitor Nogales, Michael S Piepenbrink, Jiong Wang, Sandra Ortega, Madhubanti Basu, Christopher F Fucile, John J Treanor, Alexander F Rosenberg, Martin S Zand, Michael C Keefer, Luis Martinez-Sobrido, James J Kobie
Influenza's propensity for antigenic drift and shift, and to elicit predominantly strain specific antibodies (Abs) leaves humanity susceptible to waves of new strains with pandemic potential for which limited or no immunity may exist. Subsequently new clinical interventions are needed. To identify hemagglutinin (HA) epitopes that if targeted may confer universally protective humoral immunity, we examined plasmablasts from a subject that was immunized with the seasonal influenza inactivated vaccine, and isolated a human monoclonal Ab (mAb), KPF1...
March 12, 2018: Scientific Reports
Christopher M Jenkins, Kui Yang, Gaoyuan Liu, Sung Ho Moon, Beverly G Dilthey, Richard W Gross
Plasmalogens are phospholipids critical for cell function and signaling that contain a vinyl-ether linkage at the   sn -1 position and are highly enriched in arachidonic acid (AA) at the sn -2 position. However, the enzyme(s) responsible for the cleavage of the vinyl ether linkage in plasmalogens has remained elusive.  Herein, we report that cytochrome c , in the presence of either cardiolipin (CL), O2 and H2 O2 , or oxidized CL and O2 , catalyzes the oxidation of the plasmalogen vinyl ether linkage, promoting its hydrolytic cleavage and resultant production of 2-AA-lysolipids and highly reactive α-hydroxy fatty aldehydes...
March 12, 2018: Journal of Biological Chemistry
Mayumi Kamaguchi, Hiroaki Iwata, Hideyuki Ujiie, Ken Natsuga, Wataru Nishie, Yoshimasa Kitagawa, Hiroshi Shimizu
The basement membrane zone (BMZ) consists of multiple components, including collagen XVII (COL17), which is the target of bullous pemphigoid (BP). No research has addressed the differences in BMZ components between the skin and the oral mucosa; therefore, we investigated the BMZ proteins, with a focus on COL17. The mRNA and protein expression levels of COL17 were significantly higher in oral keratinocytes (OKCs) than in skin keratinocytes (SKCs). Hemidesmosomal COL17 expression was markedly higher in OKCs than in SKCs, and its level was associated with adhesion strength...
March 9, 2018: Journal of Investigative Dermatology
Steffen Großhans, Matthias Rüdt, Adrian Sanden, Nina Brestrich, Josefine Morgenstern, Stefan Heissler, Jürgen Hubbuch
Fourier-transform infrared spectroscopy (FTIR) is a well-established spectroscopic method in the analysis of small molecules and protein secondary structure. However, FTIR is not commonly applied for in-line monitoring of protein chromatography. Here, the potential of in-line FTIR as a process analytical technology (PAT) in downstream processing was investigated in three case studies addressing the limits of currently applied spectroscopic PAT methods. A first case study exploited the secondary structural differences of monoclonal antibodies (mAbs) and lysozyme to selectively quantify the two proteins with partial least squares regression (PLS) giving root mean square errors of cross validation (RMSECV) of 2...
March 5, 2018: Journal of Chromatography. A
Agnes-Laurence Chenine, Melanie Merbah, Lindsay Wieczorek, Sebastian Molnar, Brendan Mann, Jenica Lee, Anne Marie O'Sullivan, Meera Bose, Eric Sanders-Buell, Gustavo H Kijak, Carolina Herrera, Robert McLinden, Robert J O'Connell, Nelson L Michael, Merlin L Robb, Jerome H Kim, Victoria R Polonis, Sodsai Tovanabutra
BACKGROUND: HIV-1 CRF01_AE is dominant in Thailand where RV144 vaccine trial was conducted. To study immune correlates of protection in ongoing trials, CRF01_AE derived reagents are essential. Here we present a panel of 14 HIV-1 infectious molecular clones (IMC) identified from different stages of infection, and characterization of their neutralization sensitivity using two standard assays. METHODS: One full-length IMC was constructed using a transmitted-founder virus to express Renilla luciferase (LucR) reporter gene and full-length envelopes (envs) of exogenous HIV-1...
March 8, 2018: Journal of Acquired Immune Deficiency Syndromes: JAIDS
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