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https://www.readbyqxmd.com/read/28440708/towards-in-vitro-to-in-vivo-translation-of-monoclonal-antibody-pharmacokinetics-application-of-a-neonatal-fc-receptor-mediated-transcytosis-assay-to-understand-the-interplaying-clearance-mechanisms
#1
Claudia A Castro Jaramillo, Sara Belli, Anne-Christine Cascais, Sherri Dudal, Martin R Edelmann, Markus Haak, Marie-Elise Brun, Michael B Otteneder, Mohammed Ullah, Christoph Funk, Franz Schuler, Silke Simon
Monoclonal antibodies (mAbs) are a rapidly growing drug class for which great efforts have been made to optimize certain molecular features in order to achieve the desired pharmacokinetic (PK) properties. One approach is to engineer the interactions of the mAb with the neonatal Fc receptor (FcRn) by introducing specific amino acid sequence mutations, and to assess their effect on the PK profile with in vivo studies. Indeed, FcRn protects mAbs from intracellular degradation, thereby prolongs antibody circulation time in plasma and modulates its systemic clearance...
April 25, 2017: MAbs
https://www.readbyqxmd.com/read/28421882/inhibition-of-her3-activation-and-tumor-growth-with-a-human-antibody-binding-to-a-conserved-epitope-formed-by-domain-iii-and-iv
#2
Lisa C Schmitt, Alexander Rau, Oliver Seifert, Jonas Honer, Meike Hutt, Simone Schmid, Jonas Zantow, Michael Hust, Stefan Dübel, Monilola A Olayioye, Roland E Kontermann
Human epidermal growth factor receptor 3 (HER3, also known as ErbB3) has emerged as relevant target for antibody-mediated tumor therapy. Here, we describe a novel human antibody, IgG 3-43, recognizing a unique epitope formed by domain III and parts of domain IV of the extracellular region of HER3, conserved between HER3 and mouse ErbB3. An affinity of 11 nM was determined for the monovalent interaction. In the IgG format, the antibody bound recombinant bivalent HER3 with subnanomolar affinity (KD = 220 pM) and HER3-expressing tumor cells with EC50 values in the low picomolar range (27 - 83 pM)...
April 19, 2017: MAbs
https://www.readbyqxmd.com/read/28421849/infliximab-crystal-structures-reveal-insights-into-self-association
#3
Thomas F Lerch, Penelope Sharpe, Stephen J Mayclin, Thomas E Edwards, Eunhee Lee, Hugh D Conlon, Sharon Polleck, Jason C Rouse, Yin Luo, Qin Zou
Aggregation and self-association in protein-based biotherapeutics are critical quality attributes that are tightly controlled by the manufacturing process. Aggregates have the potential to elicit immune reactions, including neutralizing anti-drug antibodies, which can diminish the drug's efficacy upon subsequent dosing. The structural basis of reversible self-association, a form of non-covalent aggregation in the native state, is only beginning to emerge for many biologics and is often unique to a given molecule...
April 19, 2017: MAbs
https://www.readbyqxmd.com/read/28406343/insights-from-native-mass-spectrometry-approaches-for-top-and-middle-level-characterization-of-site-specific-antibody-drug-conjugates
#4
Thomas Botzanowski, Stéphane Erb, Oscar Hernandez-Alba, Anthony Ehkirch, Olivier Colas, Elsa Wagner-Rousset, David Rabuka, Alain Beck, Penelope M Drake, Sarah Cianferani
Antibody-drug conjugates (ADCs) have emerged as a family of compounds with promise as efficient immunotherapies. First-generation ADCs were generated mostly via reactions on either lysine side-chain amines or cysteine thiol groups after reduction of the interchain disulfide bonds, resulting in heterogeneous populations with a variable number of drug loads per antibody. In order to control the position and the number of drug loads, new conjugation strategies aiming at the generation of more homogeneous site-specific conjugates have been developed...
April 13, 2017: MAbs
https://www.readbyqxmd.com/read/28387635/identification-of-human-igg1-variant-with-enhanced-fcrn-binding-and-without-increased-binding-to-rheumatoid-factor-autoantibody
#5
Atsuhiko Maeda, Yuki Iwayanagi, Kenta Haraya, Tatsuhiko Tachibana, Genki Nakamura, Takeru Nambu, Keiko Esaki, Kunihiro Hattori, Tomoyuki Igawa
Various studies have demonstrated that Fc engineering to enhance neonatal Fc receptor (FcRn) binding is effective for elongating half-life or increasing cellular uptake of IgG. A previous study has shown that a N434H mutation to enhance FcRn binding resulted in increased binding to rheumatoid factor (RF) autoantibody, which is not desirable for therapeutic use in autoimmune disease. In this study, we first showed that all the existing Fc variants with enhanced FcRn binding also show increased RF binding, and then identified specific mutations that could be introduced to those Fc variants to reduce the RF binding...
April 7, 2017: MAbs
https://www.readbyqxmd.com/read/28379786/unbiased-in-depth-characterization-of-cex-fractions-from-a-stressed-monoclonal-antibody-by-mass-spectrometry
#6
François Griaud, Blandine Denefeld, Manuel Lang, Héloïse Hensinger, Peter Haberl, Matthias Berg
Characterization of charge-based variants by mass spectrometry (MS) is required for the analytical development of a new biological entity and its marketing approval by health authorities. However, standard peak-based data analysis approaches are time-consuming and biased towards the detection, identification, and quantification of main variants only. The aim of this study was to characterize in-depth acidic and basic species of a stressed IgG1 monoclonal antibody using comprehensive and unbiased MS data evaluation tools...
April 5, 2017: MAbs
https://www.readbyqxmd.com/read/28379093/single-amino-acid-substitution-in-lc-cdr1-induces-russell-body-phenotype-that-attenuates-cellular-protein-synthesis-through-eif2%C3%AE-phosphorylation-and-thereby-downregulates-igg-secretion-despite-operational-secretory-pathway-traffic
#7
Haruki Hasegawa, Ann Hsu, Christine E Tinberg, Karen E Siegler, Aaron A Nazarian, Mei-Mei Tsai
Amino acid sequence differences in the variable region of immunoglobulin (Ig) cause wide variations in secretion outputs. To address how a primary sequence difference comes to modulate immunoglobulin (Ig) secretion, we investigated the biosynthetic process of two human IgG2κ monoclonal antibodies (mAbs) that differ only by one amino acid in the light chain complementarity-determining region 1 whilst showing ∼20-fold variance in secretion titer. Although poorly secreted, the lower-secreting mAb of the two was by no means defective in terms of its folding stability, antigen binding, and in vitro biologic activity...
April 5, 2017: MAbs
https://www.readbyqxmd.com/read/28368743/population-pharmacokinetics-analysis-of-vrc01-an-hiv-1-broadly-neutralizing-monoclonal-antibody-in-healthy-adults
#8
Yunda Huang, Lily Zhang, Julie Ledgerwood, Nicole Grunenberg, Robert Bailer, Abby Isaacs, Kelly Seaton, Kenneth H Mayer, Edmund Capparelli, Larry Corey, Peter B Gilbert
The monoclonal antibody VRC01 targets the CD4 binding site of the human immunodeficiency virus (HIV)-1 envelope. In the clinical study HVTN 104 (NCT02165267), 84 HIV-uninfected adults received multiple-dose intravenous (IV) VRC01 (10, 20, 30 or 40 mg/kg) every 4 or 8 weeks or subcutaneous (SC) VRC01 (5 mg/kg) every 2 weeks, and were followed for 32 weeks. We conducted a population pharmacokinetics (popPK) analysis based on 1117 VRC01 serum concentrations using a 2-compartment PK model with first-order elimination; for SC VRC01 a depot compartment with a first-order absorption rate constant was also included...
April 3, 2017: MAbs
https://www.readbyqxmd.com/read/28387583/analytical-ultracentrifugation-with-fluorescence-detection-system-reveals-differences-in-complex-formation-between-recombinant-human-tnf-and-different-biological-tnf-antagonists-in-various-environments
#9
Elena Krayukhina, Masanori Noda, Kentaro Ishii, Takahiro Maruno, Hirotsugu Wakabayashi, Minoru Tada, Takuo Suzuki, Akiko Ishii-Watabe, Masahiko Kato, Susumu Uchiyama
A number of studies have attempted to elucidate the binding mechanism between tumor necrosis factor (TNF) and clinically relevant antagonists. None of these studies, however, have been conducted as close as possible to physiologic conditions, and so the relationship between the size distribution of TNF-antagonist complexes and the antagonists' biological activity or adverse effects remains elusive. Here, we characterized the binding stoichiometry and sizes of soluble TNF-antagonist complexes for adalimumab, infliximab, and etanercept that were formed in human serum and in phosphate-buffered saline (PBS)...
May 2017: MAbs
https://www.readbyqxmd.com/read/28375048/arabinosylation-of-recombinant-human-immunoglobulin-based-protein-therapeutics
#10
Patrick Hossler, Christopher Chumsae, Christopher Racicot, David Ouellette, Alexander Ibraghimov, Daniel Serna, Alessandro Mora, Sean McDermott, Boris Labkovsky, Susanne Scesney, Christine Grinnell, Gregory Preston, Sahana Bose, Ralf Carrillo
Protein glycosylation is arguably the paramount post-translational modification on recombinant glycoproteins, and highly cited in the literature for affecting the physiochemical properties and the efficacy of recombinant glycoprotein therapeutics. Glycosylation of human immunoglobulins follows a reasonably well-understood metabolic pathway, which gives rise to a diverse range of asparagine-linked (N-linked), or serine/threonine-linked (O-linked) glycans. In N-linked glycans, fucose levels have been shown to have an inverse relationship with the degree of antibody-dependent cell-mediated cytotoxicity, and high mannose levels have been implicated in potentially increasing immunogenicity and contributing to less favorable pharmacokinetic profiles...
May 2017: MAbs
https://www.readbyqxmd.com/read/28346048/mabdelivery-administration-routes-for-antibody-therapy-third-labex-mabimprove-industrial-workshop-july-2-2015-tours-france
#11
Elsa Bodier-Montagutelli, Renaud Respaud, Hervé Watier, Audrey Guillon-Munos
The annual "LabEx MAbImprove Industrial Workshops" are primarily intended to provide a comprehensive view about topics of interest for the pharmaceutical industry to scientists involved in research on therapeutic antibodies. The third workshop in this series, held July 2, 2015 in Tours, was dedicated to the optimization of delivery, namely all processes leading monoclonal antibodies to reach their target site. The commonly used intravenous (IV) route, although advantageous in terms of pharmacokinetics and pharmacodynamics, presents some disadvantages in terms of patients' convenience, therapeutic target access or treatment cost...
May 2017: MAbs
https://www.readbyqxmd.com/read/28346045/a-modular-and-adaptive-mass-spectrometry-based-platform-for-support-of-bioprocess-development-toward-optimal-host-cell-protein-clearance
#12
Donald E Walker, Feng Yang, Joseph Carver, Koman Joe, David A Michels, X Christopher Yu
A modular and adaptive mass spectrometry (MS)-based platform was developed to provide fast, robust and sensitive host cell protein (HCP) analytics to support process development. This platform relies on one-dimensional ultra-high performance liquid chromatography (1D UHPLC) combined with several different MS data acquisition strategies to meet the needs of purification process development. The workflow was designed to allow HCP composition and quantitation for up to 20 samples per day, a throughput considered essential for real time bioprocess development support...
May 2017: MAbs
https://www.readbyqxmd.com/read/28323513/transmembrane-tnf-dependent-uptake-of-anti-tnf-antibodies
#13
Arun Deora, Subramanya Hegde, Jacqueline Lee, Chee-Ho Choi, Qing Chang, Cheryl Lee, Lucia Eaton, Hua Tang, Dongdong Wang, David Lee, Mark Michalak, Medha Tomlinson, Qingfeng Tao, Nidhi Gaur, Bohdan Harvey, Shaun McLoughlin, Boris Labkovsky, Tariq Ghayur
TNF-α (TNF), a pro-inflammatory cytokine is synthesized as a 26 kDa protein, anchors in the plasma membrane as transmembrane TNF (TmTNF), and is subjected to proteolysis by the TNF-α converting enzyme (TACE) to release the 15 kDa form of soluble TNF (sTNF). TmTNF and sTNF interact with 2 distinct receptors, TNF-R1 (p55) and TNF-R2 (p75), to mediate the multiple biologic effects of TNF described to date. Several anti-TNF biologics that bind to both forms of TNF and block their interactions with the TNF receptors are now approved for the treatment of a variety of immune-mediated diseases...
May 2017: MAbs
https://www.readbyqxmd.com/read/28306378/development-of-a-monoclonal-anti-adamts-5-antibody-that-specifically-blocks-the-interaction-with-lrp1
#14
Salvatore Santamaria, Oleg Fedorov, John McCafferty, Gillian Murphy, Jayesh Dudhia, Hideaki Nagase, Kazuhiro Yamamoto
The potent aggrecanase ADAMTS-5 is constitutively secreted by chondrocytes, but it is rapidly endocytosed in normal cartilage via the cell surface endocytic receptor LRP1. Therefore it is difficult to detect the total ADAMTS-5 activity produced. In this study, we isolated a monoclonal anti-ADAMTS-5 antibody 1B7 that blocks LRP1-mediated internalization without affecting the aggrecanolytic activity. Addition of 1B7 to cultured human chondrocytes revealed the full aggrecanolytic activity of ADAMTS-5 generated by the cells...
May 2017: MAbs
https://www.readbyqxmd.com/read/28300475/epitope-mapping-reveals-the-binding-mechanism-of-a-functional-antibody-cross-reactive-to-both-human-and-murine-programmed-death-1
#15
Dong Li, Jianqing Xu, Zhuozhi Wang, Zhen Gong, Jieying Liu, Yong Zheng, Jian Li, Jing Li
Of the inhibitory checkpoints in the immune system, programmed death 1 (PD-1) is one of the most promising targets for cancer immunotherapy. The anti-PD-1 antibodies currently approved for clinical use or under development bind to human PD-1 (hPD-1), but not murine PD-1. To facilitate studies in murine models, we developed a functional antibody against both human and murine PD-1, and compared the epitopes of such antibody to a counterpart that only bound to hPD-1. To quickly identify the epitopes of the 2 antibodies, we used alanine scanning and mammalian cell expression cassette...
May 2017: MAbs
https://www.readbyqxmd.com/read/28296619/drifts-in-adcc-related-quality-attributes-of-herceptin%C3%A2-impact-on-development-of-a-trastuzumab-biosimilar
#16
Seokkyun Kim, Jinsu Song, Seungkyu Park, Sunyoung Ham, Kyungyeol Paek, Minjung Kang, Yunjung Chae, Heewon Seo, Hyung-Chan Kim, Michael Flores
A biosimilar product needs to demonstrate biosimilarity to the originator reference product, and the quality profile of the latter should be monitored throughout the period of the biosimilar's development to match the quality attributes of the 2 products that relate to efficacy and safety. For the development of a biosimilar version of trastuzumab, the reference product, Herceptin®, was extensively characterized for the main physicochemical and biologic properties by standard or state-of-the-art analytical methods, using multiple lots expiring between March 2015 and December 2019...
May 2017: MAbs
https://www.readbyqxmd.com/read/28287337/generation-and-characterization-of-protective-antibodies-to-marburg-virus
#17
Jeffrey W Froude, Thibaut Pelat, Sebastian Miethe, Samantha E Zak, Anna Z Wec, Kartik Chandran, Jennifer Mary Brannan, Russell R Bakken, Michael Hust, Philippe Thullier, John M Dye
Marburg virus (MARV) and Ebola virus (EBOV) have been a source of epidemics and outbreaks for several decades. We present here the generation and characterization of the first protective antibodies specific for wild-type MARV. Non-human primates (NHP), cynomolgus macaques, were immunized with viral-replicon particles expressing the glycoproteins (GP) of MARV (Ci67 isolate). An antibody fragment (single-chain variable fragment, scFv) phage display library was built after four immunogen injections, and screened against the GP1-649 of MARV...
May 2017: MAbs
https://www.readbyqxmd.com/read/28281887/rapid-assessment-of-oxidation-via-middle-down-lcms-correlates-with-methionine-side-chain-solvent-accessible-surface-area-for-121-clinical-stage-monoclonal-antibodies
#18
Rong Yang, Tushar Jain, Heather Lynaugh, R Paul Nobrega, Xiaojun Lu, Todd Boland, Irina Burnina, Tingwan Sun, Isabelle Caffry, Michael Brown, Xiaoyong Zhi, Asparouh Lilov, Yingda Xu
Susceptibility of methionine to oxidation is an important concern for chemical stability during the development of a monoclonal antibody (mAb) therapeutic. To minimize downstream risks, leading candidates are usually screened under forced oxidation conditions to identify oxidation-labile molecules. Here we report results of forced oxidation on a large set of in-house expressed and purified mAbs with variable region sequences corresponding to 121 clinical stage mAbs. These mAb samples were treated with 0.1% H2O2 for 24 hours before enzymatic cleavage below the hinge, followed by reduction of inter-chain disulfide bonds for the detection of the light chain, Fab portion of heavy chain (Fd) and Fc by liquid chromatography-mass spectrometry...
May 2017: MAbs
https://www.readbyqxmd.com/read/28281873/resolving-the-micro-heterogeneity-and-structural-integrity-of-monoclonal-antibodies-by-hybrid-mass-spectrometric-approaches
#19
Yang Yang, Guanbo Wang, Ting Song, Carlito B Lebrilla, Albert J R Heck
For therapeutic monoclonal antibodies (mAbs), detailed analysis of the structural integrity and heterogeneity, which results from multiple types of post-translational modifications (PTMs), is relevant to various processes, including product characterization, storage stability and quality control. Despite the recent rapid development of new bioanalytical techniques, it is still challenging to completely characterize the proteoform profile of a mAb. As a nearly indispensable tool in mAb analysis, mass spectrometry (MS) provides unique structural information at multiple levels...
May 2017: MAbs
https://www.readbyqxmd.com/read/28281872/novel-anti-sialyl-tn-monoclonal-antibodies-and-antibody-drug-conjugates-demonstrate-tumor-specificity-and-anti-tumor-activity
#20
Jillian M Prendergast, Ana Paula Galvao da Silva, David A Eavarone, Darius Ghaderi, Mai Zhang, Dane Brady, Joan Wicks, Julie DeSander, Jeff Behrens, Bo R Rueda
Targeted therapeutics that can differentiate between normal and malignant tumor cells represent the ideal standard for the development of a successful anti-cancer strategy. The Sialyl-Thomsen-nouveau antigen (STn or Sialyl-Tn, also known as CD175s) is rarely seen in normal adult tissues, but it is abundantly expressed in many types of human epithelial cancers. We have identified novel antibodies that specifically target with high affinity the STn glycan independent of its carrier protein, affording the potential to recognize a wider array of cancer-specific sialylated proteins...
May 2017: MAbs
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