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https://www.readbyqxmd.com/read/28102754/enhancement-of-antibody-functions-through-fc-multiplications
#1
Qun Wang, Yan Chen, Mark Pelletier, Romana Cvitkovic, Jessica Bonnell, Chien-Ying Chang, Adem C Koksal, Ellen O'Connor, Xizhe Gao, Xiang-Qing Yu, Herren Wu, C Kendall Stover, William F Dall'Acqua, Xiaodong Xiao
Antibodies carry out a plethora of functions through their crystallizable fragment (Fc) regions, which can be naturally tuned by the adoption of several isotypes and post-translational modifications. Protein engineering enables further Fc function modulations through modifications of the interactions between the Fc and its functional partners, including FcγR, FcRn, complement complex, and additions of auxiliary functional units. Due to the many functions embedded within the confinement of an Fc, a suitable balance must be maintained for a therapeutic antibody to be effective and safe...
January 19, 2017: MAbs
https://www.readbyqxmd.com/read/28095113/quantitative-analysis-of-cell-surface-antigen-antibody-interaction-using-gaussia-princeps-luciferase-antibody-fusion-proteins
#2
Juliane Kums, Johannes Nelke, Benedikt Rüth, Viktoria Schäfer, Daniela Siegmund, Harald Wajant
Cell surface antigen-specific antibodies are of substantial diagnostic and therapeutic importance. The binding properties of such antibodies are usually evaluated by cell-free assays, in particular surface plasmon resonance (SPR) analysis, or flow cytometry. SPR analyses allow the detailed quantitative and dynamic evaluation of the binding properties of antibodies, but need purified, typically recombinantly produced antigens. It can, however, be difficult to produce the required antigen. Furthermore, cellular factors influencing the antigen-antibody interaction are not considered by this method...
January 17, 2017: MAbs
https://www.readbyqxmd.com/read/28075201/corrigendum
#3
(no author information available yet)
No abstract text is available yet for this article.
January 11, 2017: MAbs
https://www.readbyqxmd.com/read/28071970/the-making-of-bispecific-antibodies
#4
Ulrich Brinkmann, Roland E Kontermann
During the past two decades we have seen a phenomenal evolution of bispecific antibodies for therapeutic applications. The 'zoo' of bispecific antibodies is populated by many different species, comprising around 100 different formats, including small molecules composed solely of the antigen-binding sites of two antibodies, molecules with an IgG structure, and large complex molecules composed of different antigen-binding moieties often combined with dimerization modules. The application of sophisticated molecular design and genetic engineering has solved many of the technical problems associated with the formation of bispecific antibodies such as stability, solubility and other parameters that confer drug properties...
January 10, 2017: MAbs
https://www.readbyqxmd.com/read/28055305/generation-of-a-highly-diverse-panel-of-antagonistic-chicken-monoclonal-antibodies-against-the-gip-receptor
#5
Jennifer D Könitzer, Shreya Pramanick, Qi Pan, Robert Augustin, Sebastian Bandholtz, William Harriman, Shelley Izquierdo
Raising functional antibodies against G protein-coupled receptors (GPCRs) is challenging due to their low density expression, instability in the absence of the cell membrane's lipid bilayer and frequently short extracellular domains that can serve as antigens. In addition, a particular therapeutic concept may require an antibody to not just bind the receptor, but also act as a functional receptor agonist or antagonist. Antagonizing the glucose-dependent insulinotropic polypeptide (GIP) receptor may open up new therapeutic modalities in the treatment of diabetes and obesity...
January 5, 2017: MAbs
https://www.readbyqxmd.com/read/28055299/guiding-bispecific-monovalent-antibody-formation-through-proteolysis-of-igg1-single-chain
#6
Nazzareno Dimasi, Ryan Fleming, Kris F Sachsenmeier, Binyam Bezabeh, Carl Hay, Jincheng Wu, Erin Sult, Saravanan Rajan, Li Zhuang, Peter Cariuk, Andrew Buchanan, Michael A Bowen, Herren Wu, Changshou Gao
We developed an IgG1 domain-tethering approach to guide the correct assembly of two light and two heavy chains, derived from two different antibodies, to form bispecific monovalent antibodies in IgG1 format. We show here that assembling two different light and heavy chains by sequentially connecting them with protease-cleavable polypeptide linkers results in the generation of monovalent bispecific antibodies that have IgG1 sequence, structure and functional properties. This approach was used to generate a bispecific monovalent antibody targeting the epidermal growth factor receptor and the type I insulin-like growth factor receptor that: 1) can be produced and purified using standard IgG1 techniques; 2) exhibits stability and structural features comparable to IgG1; 3) binds both targets simultaneously; and 4) has potent anti-tumor activity...
January 5, 2017: MAbs
https://www.readbyqxmd.com/read/28055297/a-strategy-to-identify-linker-based-modules-for-the-allosteric-regulation-of-antibody-antigen-binding-affinities-of-different-scfvs
#7
Sarah-Jane Kellmann, Stefan Dübel, Holger Thie
Antibody single-chain variable fragments (scFvs) are used in a variety of applications, such as for research, diagnosis and therapy. Essential for these applications is the extraordinary specificity, selectivity and affinity of antibody paratopes, which can also be employed for efficient protein purification. However, this use is hampered by the high affinity for the protein to be purified because harsh elution conditions, which may impair folding, integrity or viability of the eluted biomaterials, are typically required...
January 5, 2017: MAbs
https://www.readbyqxmd.com/read/28055295/igg-fc-variant-cross-reactivity-between-human-and-rhesus-macaque-fc%C3%AE-rs
#8
Austin W Boesch, Adam R Miles, Ying N Chan, Nana Y Osei-Owusu, Margaret E Ackerman
Non-human primate (NHP) studies are often an essential component of antibody development efforts prior to human trials. Because the efficacy or toxicity of candidate antibodies may depend on their interactions with Fcγ receptors (FcγR) and their resulting ability to induce FcγR-mediated effector functions such as antibody-dependent cell-meditated cytotoxicity and phagocytosis (ADCP), the evaluation of human IgG variants with modulated affinity towards human FcγR is becoming more prevalent in both infectious disease and oncology studies in NHP...
January 5, 2017: MAbs
https://www.readbyqxmd.com/read/28005456/physicochemical-and-biological-characterization-of-sb2-a-biosimilar-of-remicade%C3%A2-infliximab
#9
Juyong Hong, Yuhwa Lee, Changsoo Lee, Suhyeon Eo, Soyeon Kim, Nayoung Lee, Jongmin Park, Seungkyu Park, Donghyuck Seo, Min Jeong, Youngji Lee, Soojeong Yeon, George Bou-Assaf, Zoran Sosic, Wei Zhang, Orlando Jaquez
A biosimilar is a biological medicinal product that contains a version of the active substance of an already authorized original biological medicinal product. Biosimilarity to the reference product (RP) in terms of quality characteristics, such as physicochemical and biological properties, safety, and efficacy, based on a comprehensive comparability exercise needs to be established. SB2 (Flixabi® and Renflexis®) is a biosimilar to Remicade® (infliximab). The development of SB2 was performed in accordance with relevant guidelines of the International Conference on Harmonisation, the European Medicines Agency, and the United States Food and Drug Administration...
December 22, 2016: MAbs
https://www.readbyqxmd.com/read/28001487/impact-of-spr-biosensor-assay-configuration-on-antibody-neonatal-fc-receptor-binding-data
#10
Xiangdan Wang, Patrick McKay, Liliana T Yee, George Dutina, Philip E Hass, Ihsan Nijem, David Allison, Kyra J Cowan, Kevin Lin, Valerie Quarmby, Jihong Yang
Binding interactions with the neonatal Fc receptor (FcRn) are one determinant of pharmacokinetic properties of recombinant human monoclonal antibody (rhumAb) therapeutics, and a conserved binding motif in the crystallizable fragment (Fc) region of IgG molecules interacts with FcRn. Surface plasmon resonance (SPR) biosensor assays are often used to characterize interactions between FcRn and rhumAb therapeutics. In such assays, generally either the rhumAb (format 1) or the FcRn protein (format 2) is immobilized on a biosensor chip...
December 21, 2016: MAbs
https://www.readbyqxmd.com/read/28001485/optimizing-assembly-and-production-of-native-bispecific-antibodies-by-codon-de-optimization
#11
Giovanni Magistrelli, Yves Poitevin, Florence Schlosser, Guillemette Pontini, Pauline Malinge, Soheila Josserand, Marie Corbier, Nicolas Fischer
When production of bispecific antibodies requires the co-expression and assembly of three or four polypeptide chains, low expression of one chain can significantly limit assembly and yield. κλ bodies, fully human bispecific antibodies with native IgG structure, are composed of a common heavy chain and two different light chains, one kappa and one lambda. No engineering is applied to force pairing of the chains, thus both monospecific and bispecific antibodies are secreted in the supernatant. In this context, stoichiometric expression of the two light chains allows for maximal assembly of the bispecific antibody...
December 21, 2016: MAbs
https://www.readbyqxmd.com/read/27996375/trimeric-gp120-specific-bovine-monoclonal-antibodies-require-cysteine-and-aromatic-residues-in-cdrh3-for-high-affinity-binding-to-hiv-env
#12
Behnaz Heydarchi, Rob J Center, Jonathan Bebbington, Jack Cuthbertson, Christopher Gonelli, Georges Khoury, Charlene Mackenzie, Marit Lichtfuss, Grant Rawlin, Brian Muller, Damian Purcell
We isolated HIV-1 Envelope (Env)-specific memory B cells from a cow that had developed high titre polyclonal immunoglobulin G (IgG) with broad neutralizing activity after a long duration vaccination with HIV-1AD8 Env gp140 trimers. We cloned the bovine IgG matched heavy (H) and light (L) chain variable (V) genes from these memory B cells and constructed IgG monoclonal antibodies (mAbs) with either a human constant (C)-region/bovine V-region chimeric or fully bovine C and V regions. Among 42 selected Ig+ memory B cells, two mAbs (6A and 8C) showed high affinity binding to gp140 Env...
December 20, 2016: MAbs
https://www.readbyqxmd.com/read/27981887/insertion-of-scfv-into-the-hinge-domain-of-full-length-igg1-monoclonal-antibody-results-in-tetravalent-bispecific-molecule-with-robust-properties
#13
Binyam Bezabeh, Ryan Fleming, Christine Fazenbaker, Haihong Zhong, Karen Coffman, Xiang-Qing Yu, Ching Ching Leow, Nerea Gibson, Susan Wilson, C Kendall Stover, Herren Wu, Changshou Gao, Nazzareno Dimasi
By simultaneous binding two disease mediators, bispecific antibodies offer the opportunity to broaden the utility of antibody-based therapies. Herein, we describe the design and characterization of Bs4Ab, an innovative and generic bispecific tetravalent antibody platform. The Bs4Ab format comprises a full-length IgG1 monoclonal antibody with a scFv inserted into the hinge domain. The Bs4Ab design demonstrates robust manufacturability, as evidenced by MEDI3902, which is currently in clinical development. To further demonstrate the applicability of the Bs4Ab technology, we describe the molecular engineering, biochemical, biophysical, and in vivo characterization of a bispecific tetravalent Bs4Ab that, by simultaneously binding vascular endothelial growth factor and angiopoietin-2, inhibits their function...
December 16, 2016: MAbs
https://www.readbyqxmd.com/read/27981884/quantitative-characterization-of-the-mechanism-of-action-and-impact-of-a-proteolysis-permitting-anti-pcsk9-antibody
#14
Ryan J Hansen, Michael J Berna, Andrea E Sperry, Thomas P Beyer, Victor J Wroblewski, Krista M Schroeder, Patrick I Eacho
A recent report described a novel mechanism of action for an anti-proprotein convertase subtilisin-kexin type 9 (PCSK9) monoclonal antibody (LY3015014, or LY), wherein the antibody has improved potency and duration of action due to the PCSK9 epitope for LY binding. Unlike other antibodies, proteolysis of PCSK9 can occur when LY is bound to PCSK9. We hypothesized that this allowance of PCSK9 cleavage potentially improves LY efficiency through two pathways, namely lack of accumulation of intact PCSK9 and reduced clearance of LY...
December 16, 2016: MAbs
https://www.readbyqxmd.com/read/27960628/antibodies-to-watch-in-2017
#15
Janice M Reichert
Over 50 investigational monoclonal antibody (mAb) therapeutics are currently undergoing evaluation in late-stage clinical studies, which is expected to drive a trend toward first marketing approvals of at least 6-9 mAbs per year in the near-term. In the United States (US), a total of 6 and 9 mAbs were granted first approvals during 2014 and 2015, respectively; all these products are also approved in the European Union (EU). As of December 1, 2016, 6 mAbs (atezolizumab, olaratumab, reslizumab, ixekizumab, bezlotoxumab, oblitoxaximab) had been granted first approvals during 2016 in either the EU or US...
December 14, 2016: MAbs
https://www.readbyqxmd.com/read/27937066/purification-of-common-light-chain-igg-like-bispecific-antibodies-using-highly-linear-ph-gradients
#16
Beth Sharkey, Sarat Pudi, Ian Wallace Moyer, Lihui Zhong, Bianka Prinz, Hemanta Baruah, Heather Lynaugh, Sampath Kumar, K Dane Wittrup, Juergen H Nett
Monovalent bispecific antibodies (BsAbs) are projected to have broad clinical applications due to their ability to bind two different targets simultaneously. Although they can be produced using recombinant technologies, the correct pairing of heavy and light chains is a significant manufacturing problem. Various approaches exploit mutations or linkers to favor the formation of the desired BsAb, but a format using a single common light chain has the advantage that no other modification to the antibody is required...
December 12, 2016: MAbs
https://www.readbyqxmd.com/read/27929753/generation-and-characterization-of-abbv642-a-dual-variable-domain-immunoglobulin-molecule-dvd-ig-that-potently-neutralizes-vegf-and-pdgf-bb-and-is-designed-for-the-treatment-of-exudative-age-related-macular-degeneration
#17
Kun Ding, Lucia Eaton, Diana Bowley, Matthew Rieser, Qing Chang, Maria C Harris, Anca Clabbers, Feng Dong, Jikui Shen, Sean F Hackett, Debra S Touw, Jacqueline Bixby, Suju Zhong, Lorenzo Benatuil, Sahana Bose, Christine Grinnell, Gregory M Preston, Ramesh Iyer, Ramkrishna Sadhukhan, Susan Marchie, Gary Overmeyer, Tariq Ghayur, Deborah A van Riet, Shibo Tang, Peter A Campochario, Jijie Gu
Exudative age-related macular degeneration (AMD) is the most common cause of moderate and severe vision loss in developed countries. Intraocular injections of vascular endothelial growth factor (VEGF or VEGF-A)-neutralizing proteins provide substantial benefit, but frequent, long-term injections are needed. In addition, many patients experience initial visual gains that are ultimately lost due to subretinal fibrosis. Preclinical studies and early phase clinical trials suggest that combined suppression of VEGF and platelet-derived growth factor-BB (PDGF-BB) provides better outcomes than suppression of VEGF alone, due to more frequent regression of neovascularization (NV) and suppression of subretinal fibrosis...
December 8, 2016: MAbs
https://www.readbyqxmd.com/read/27929752/efficient-production-of-bispecific-igg-of-different-isotypes-and-species-of-origin-in-single-mammalian-cells
#18
Michael Dillon, Yiyuan Yin, Jianhui Zhou, Luke McCarty, Diego Ellerman, Dionysos Slaga, Teemu T Junttila, Guanghui Han, Wendy Sandoval, Meric A Ovacik, Kedan Lin, Zhilan Hu, Amy Shen, Jacob E Corn, Christoph Spiess, Paul J Carter
Bispecific IgG production in single host cells has been a much sought-after goal to support the clinical development of these complex molecules. Current routes to single cell production of bispecific IgG include engineering heavy chains for heterodimerization and redesign of Fab arms for selective pairing of cognate heavy and light chains. Here, we describe novel designs to facilitate selective Fab arm assembly in conjunction with previously described knobs-into-holes mutations for preferential heavy chain heterodimerization...
December 8, 2016: MAbs
https://www.readbyqxmd.com/read/27929747/localized-conformational-interrogation-of-antibody-and-antibody-drug-conjugates-by-site-specific-carboxyl-group-footprinting
#19
Lucy Yan Pan, Oscar Salas-Solano, John F Valliere-Douglass
Establishing and maintaining conformational integrity of monoclonal antibodies (mAbs) and antibody-drug conjugates (ADCs) during development and manufacturing is critical for ensuring their clinical efficacy. As presented here, we applied site-specific carboxyl group footprinting (CGF) for localized conformational interrogation of mAbs. The approach relies on covalent labeling that introduces glycine ethyl ester tags onto solvent-accessible side chains of protein carboxylates. Peptide mapping is used to monitor the labeling kinetics of carboxyl residues and the labeling kinetics reflects the conformation or solvent-accessibility of side chains...
December 8, 2016: MAbs
https://www.readbyqxmd.com/read/27929745/an-elaborate-landscape-of-the-human-antibody-repertoire-against-enterovirus-71-infection-is-revealed-by-phage-display-screening-and-deep-sequencing
#20
Zhe Chen, Xianwen Ren, Jian Yang, Jie Dong, Ying Xue, Lilian Sun, Yafang Zhu, Qi Jin
Enterovirus 71 (EV71) causes outbreaks of hand, foot and mouth disease (HFMD), primarily in the Asia-Pacific area, that are often associated with complications of severe to fatal neurological symptoms. There are currently no anti-viral therapies or vaccines available for the treatment of EV71 infection. Illustrating human antibody responses neutralizing EV71 infection could potentially provide valuable information for the development of effective therapies and vaccines. Here, we constructed a comprehensive phage display library based on peripheral blood of eight EV71-infected donors and identified 27 EV71-specific human antibodies, of which four have neutralizing activity in in vitro experiments...
December 8, 2016: MAbs
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