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https://www.readbyqxmd.com/read/28541812/engineering-humanized-antibody-framework-sequences-for-optimal-site-specific-conjugation-of-cytotoxins
#1
Jared L Spidel, Earl F Albone, Xin Cheng, Benjamin Vaessen, Sara Jacob, Andrew Z Milinichik, Arielle Verdi, J Bradford Kline, Luigi Grasso
The prevailing techniques used to generate antibody-drug conjugates (ADCs) involve random conjugation of the linker-drug to multiple lysines or cysteines in the antibody. Engineering natural and non-natural amino acids into an antibody has been demonstrated to be an effective strategy to produce homogeneous ADC products with defined drug-to-antibody ratios. We recently reported an efficient residue-specific conjugation technology (RESPECT) where thiol-reactive payloads can be efficiently conjugated to a native unpaired cysteine in position 80 (C80) of rabbit light chains...
May 25, 2017: MAbs
https://www.readbyqxmd.com/read/28506197/high-resolution-mass-spectrometry-confirms-the-presence-of-a-hydroxyproline-hyp-post-translational-modification-in-the-ggggp-linker-of-an-fc-fusion-protein
#2
Chris Spahr, Gunasekaran Kannan, Kenneth W Walker, Stone D-H Shi
Flexible and protease resistant (G4S)n linkers are used extensively in protein engineering to connect various protein domains. Recently, a number of groups have observed xylose-based O-glycosylation at linker Ser residues that yield unwanted heterogeneity and may affect product quality. Because of this, an engineering effort was implemented to explore different linker sequence constructs. Here, we demonstrate the presence of an unexpected hydroxylation of a prolyl residue in the linker, made possible through the use of high-resolution mass spectrometry (HR-MS) and MSn...
May 16, 2017: MAbs
https://www.readbyqxmd.com/read/28475474/antibodies-targeting-g-protein-coupled-receptors-recent-advances-and-therapeutic-challenges
#3
Mohammed Akli Ayoub, Pascale Crépieux, Markus Koglin, Marc Parmentier, Jean-Philippe Pin, Anne Poupon, Eric Reiter, Martine Smit, Jan Steyaert, Hervé Watier, Trevor Wilkinson
Le STUDIUM conference was held November 24-25, 2016 in Tours, France as a satellite workshop of the 5(th) meeting of the French GDR 3545 on "G Protein-Coupled Receptors (GPCRs) - From Physiology to Drugs", which was held in Tours during November 22-24, 2016. The conference gathered speakers from academia and industry considered to be world leaders in the molecular pharmacology and signaling of GPCRs, with a particular interest in the development of therapeutic GPCR antibodies (Abs). The main topics were new advances and challenges in the development of antibodies targeting GPCRs and their potential applications to the study of the structure and function of GPCRs, as well as their implication in physiology and pathophysiology...
May 5, 2017: MAbs
https://www.readbyqxmd.com/read/28475417/challenges-and-opportunities-for-the-future-of-monoclonal-antibody-development-improving-safety-assessment-and-reducing-animal-use
#4
Fiona Sewell, Kathryn Chapman, Jessica Couch, Maggie Dempster, Shawn Heidel, Lise Loberg, Curtis Maier, Tim K McLachlan, Marque Todd, Jan Willem van der Laan
The market for biotherapeutic monoclonal antibodies (mAbs) is large and is growing rapidly. However, attrition poses a significant challenge for the development of mAbs, and for biopharmaceuticals in general, with large associated costs in resource and animal use. Termination of candidate mAbs may occur due to poor translation from preclinical models to human safety. It is critical that the industry addresses this problem in order to maintain productivity. Though attrition poses a significant challenge for pharmaceuticals in general, there are specific challenges related to the development of antibody-based products...
May 5, 2017: MAbs
https://www.readbyqxmd.com/read/28463063/pharmacokinetic-de-risking-tools-for-selection-of-monoclonal-antibody-lead-candidates
#5
Miroslav Dostalek, Thomayant Prueksaritanont, Robert F Kelley
Pharmacokinetic studies play an important role in all stages of drug discovery and development. Recent advancements in the tools for discovery and optimization of therapeutic proteins have created an abundance of candidates that may fulfill target product profile criteria. Implementing a set of in silico, small scale in vitro and in vivo tools can help to identify a clinical lead molecule with promising properties at the early stages of drug discovery, thus reducing the labor and cost in advancing multiple candidates towards clinical development...
May 2, 2017: MAbs
https://www.readbyqxmd.com/read/28463043/affinity-of-human-igg-subclasses-to-mouse-fc-gamma-receptors
#6
Gillian Dekkers, Arthur E H Bentlage, Tamara C Stegmann, Heather L Howie, Suzanne Lissenberg-Thunnissen, James Zimring, Theo Rispens, Gestur Vidarsson
Human IgG is the main antibody class used in antibody therapies because of its efficacy and longer half-life, which are completely or partly due to FcγR-mediated functions of the molecules. Preclinical testing in mouse models are frequently performed using human IgG, but no detailed information on binding of human IgG to mouse FcγRs is available. The orthologous mouse and human FcγRs share roughly 60-70% identity, suggesting some incompatibility. Here, we report binding affinities of all mouse and human IgG subclasses to mouse FcγR...
May 2, 2017: MAbs
https://www.readbyqxmd.com/read/28440708/toward-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
#7
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 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
#8
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
#9
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
#10
Thomas Botzanowski, Stéphane Erb, Oscar Hernandez-Alba, Anthony Ehkirch, Olivier Colas, Elsa Wagner-Rousset, David Rabuka, Alain Beck, Penelope M Drake, Sarah Cianférani
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. 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
#11
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
#12
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
#13
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
#14
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
#15
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
#16
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
#17
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
#18
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
#19
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
#20
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
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