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https://www.readbyqxmd.com/read/28816592/two-faced-fcab-prevents-polymerization-with-vegf-and-reveals-thermodynamics-and-the-2-15%C3%A2-%C3%A3-crystal-structure-of-the-complex
#1
Elisabeth Lobner, Anne-Sophie Humm, Georg Mlynek, Konstantin Kubinger, Michael Kitzmüller, Michael W Traxlmayr, Kristina Djinović-Carugo, Christian Obinger
Fcabs (Fc domain with antigen-binding sites) are promising novel therapeutics. By engineering of the C-terminal loops of the CH3 domains, two antigen binding sites can be inserted in close proximity. In order to elucidate the binding mode(s) between homodimeric Fcabs and small homodimeric antigens, the interaction between the Fcabs 448 and CT6 (having the AB, CD and EF loops and the C-termini engineered) with homodimeric VEGF was investigated. The crystal structures of these Fcabs, which form polymers with the antigen VEGF in solution, were determined...
August 17, 2017: MAbs
https://www.readbyqxmd.com/read/28816583/mammalian-cell-surface-display-for-monoclonal-antibody-based-facs-selection-of-viral-envelope-proteins
#2
Tim-Henrik Bruun, Veronika Grassmann, Benjamin Zimmer, Benedikt Asbach, David Peterhoff, Alexander Kliche, Ralf Wagner
The elicitation of broadly and efficiently neutralizing antibodies in humans by active immunization is still a major obstacle in the development of vaccines against pathogens such as the human immunodeficiency virus (HIV), influenza virus, hepatitis C virus or cytomegalovirus. Here, we describe a mammalian cell surface display and monoclonal antibody (mAb)-mediated panning technology that allows affinity-based selection of envelope (Env) variants from libraries. To this end, we established an experimental setup featuring: 1) single and site specific integration of Env to link genotype and phenotype, 2) inducible Env expression to avoid cytotoxicity effects, 3) translational coupling of Env and enhanced green fluorescent protein expression to normalize for Env protein levels, and 4) display on HEK cells to ensure native folding and mammalian glycosylation...
August 17, 2017: MAbs
https://www.readbyqxmd.com/read/28812955/igg-cooperativity-is-there-allostery-implications-for-antibody-functions-and-therapeutic-antibody-development
#3
Danlin Yang, Rachel Kroe-Barrett, Sanjaya Singh, Christopher J Roberts, Thomas M Laue
A central dogma in immunology is that an antibody's in vivo functionality is mediated by two independent events: antigen binding by the variable (V) region, followed by effector activation by the constant (C) region. However, this view has recently been challenged by reports suggesting allostery exists between the two regions, triggered by conformational changes or configurational differences. The possibility of allosteric signals propagating through the IgG domains complicates our understanding of the antibody structure-function relationship, and challenges the current subclass selection process in therapeutic antibody design...
August 16, 2017: MAbs
https://www.readbyqxmd.com/read/28805536/a-quadrupole-dalton-based-multi-attribute-method-for-product-characterization-process-development-and-quality-control-of-therapeutic-proteins
#4
Weichen Xu, Rod Brian Jimenez, Rachel Mowery, Haibin Luo, Mingyan Cao, Nitin Agarwal, Irina Ramos, Xiangyang Wang, Jihong Wang
No abstract text is available yet for this article.
August 14, 2017: MAbs
https://www.readbyqxmd.com/read/28805498/gingiskhan%C3%A2-protease-cleavage-allows-a-high-throughput-antibody-to-fab-conversion-enabling-direct-functional-assessment-during-lead-identification-of-human-monoclonal-and-bispecific-igg1-antibodies
#5
Jörg Moelleken, Manuel Endesfelder, Christian Gassner, Sabine Lingke, Simone Tomaschek, Oksana Tyshchuk, Stefan Lorenz, Ulrike Reiff, Michael Mølhøj
The determination of the binding strength of immunoglobulins (IgGs) to targets can be influenced by avidity when the targets are soluble di- or multimeric proteins, or associated to cell surfaces, including surfaces introduced from heterogeneous assays. However, for the understanding of the contribution of a second drug-to-target binding site in molecular design, or for ranking of monovalent binders during lead identification, affinity-based assessment of the binding strength is required. Typically, monovalent binders like antigen-binding fragments (Fabs) are generated by proteolytic cleavage with papain, which often results in a combination of under- and over-digestion, and requires specific optimization and chromatographic purification of the desired Fabs...
August 14, 2017: MAbs
https://www.readbyqxmd.com/read/28787231/biosimilarity-under-stress-a-forced-degradation-study-of-remicade%C3%A2-and-remsima%C3%A2
#6
Karthik Pisupati, Alexander Benet, Yuwei Tian, Solomon Okbazghi, Jukyung Kang, Michael Ford, Sergei Saveliev, K Ilker Sen, Eric Carlson, Thomas J Tolbert, Brandon T Ruotolo, Steven P Schwendeman, Anna Schwendeman
Remsima™ (infliximab) is the first biosimilar monoclonal antibody (mAb) approved by the European Medical Agency and the US Food and Drug Administration. Remsima™ is highly similar to its reference product, Remicade®, with identical formulation components. The two products, however, are not identical; Remsima™ has higher levels of soluble aggregates, C-terminal lysine truncation, and fucosylated glycans. In order to understand if these attribute differences could be amplified during forced degradation, solutions and lyophilized powders of the two products were subjected to stress at elevated temperature (40-60°C) and humidity (dry-97% relative humidity)...
August 8, 2017: MAbs
https://www.readbyqxmd.com/read/28786732/maximizing-in-vivo-target-clearance-by-design-of-ph-dependent-target-binding-antibodies-with-altered-affinity-to-fcrn
#7
Danlin Yang, Craig Giragossian, Steven Castellano, Marcio Lasaro, Haiguang Xiao, Himanshu Saraf, Cynthia Hess Kenny, Irina Rybina, Zhong-Fu Huang, Jennifer Ahlberg, Tammy Bigwarfe, Maria Myzithras, Erica Waltz, Simon Roberts, Rachel Kroe-Barrett, Sanjaya Singh
Antibodies with pH-dependent binding to both target antigens and neonatal Fc receptor (FcRn) provide an alternative tool to conventional neutralizing antibodies, particularly for therapies where reduction in antigen level is challenging due to high target burden. However, the requirements for optimal binding kinetic framework and extent of pH dependence for these antibodies to maximize target clearance from circulation are not well understood. We have identified a series of naturally-occurring high affinity antibodies with pH-dependent target binding properties...
August 8, 2017: MAbs
https://www.readbyqxmd.com/read/28758875/functional-optimization-of-agonistic-antibodies-to-ox40-receptor-with-novel-fc-mutations-to-promote-antibody-multimerization
#8
Di Zhang, Anthony A Armstrong, Susan H Tam, Stephen G McCarthy, Jinquan Luo, Gary L Gilliland, Mark L Chiu
Immunostimulatory receptors belonging to the tumor necrosis factor receptor (TNFR) superfamily are emerging as promising targets for cancer immunotherapies. To optimize the agonism of therapeutic antibodies to these receptors, Fc engineering of antibodies was applied to facilitate the clustering of cell surface TNFRs to activate downstream signaling pathways. One engineering strategy is to identify Fc mutations that facilitate antibody multimerization on the cell surface directly. From the analyses of the crystal packing of IgG1 structures, we identified a novel set of Fc mutations, T437R and K248E, that facilitated antibody multimerization upon binding to antigens on cell surface...
July 31, 2017: MAbs
https://www.readbyqxmd.com/read/28758834/preferential-interactions-of-trehalose-l-arginine-hcl-and-sodium-chloride-with-therapeutically-relevant-igg1-monoclonal-antibodies
#9
Chaitanya Sudrik, Theresa Cloutier, Phuong Pham, Hardeep S Samra, Bernhardt L Trout
Preferential interactions of weakly interacting formulation excipients govern their effect on the equilibrium and kinetics of several reactions of protein molecules in solution. Using vapor pressure osmometry, we characterized the preferential interactions of commonly used excipients trehalose, L-arginine.HCl and NaCl with three therapeutically-relevant, IgG1 monoclonal antibodies that have similar size and shape, but differ in their surface hydrophobicity and net charge. We further characterized the effect of these excipients on the reversible self-association, aggregation and viscosity behavior of these antibody molecules...
July 31, 2017: MAbs
https://www.readbyqxmd.com/read/28745541/chaperone-proteins-as-single-component-reagents-to-assess-antibody-nonspecificity
#10
Ryan L Kelly, James C Geoghegan, Jared Feldman, Tushar Jain, Monique Kauke, Doris Le, Jessie Zhao, K Dane Wittrup
Early stage assays that evaluate monoclonal antibody drug-like properties serve as valuable tools for selection of lead candidates. One liability for clinical development, off-target reactivity, is often assessed by binding to a mixture or panel of noncognate proteins. While robust, these mixes are often ill-defined, and can suffer from issues such as lot-to-lot variability. In this study, we discovered in immunoprecipitation experiments that certain chaperones are present in one of these mixtures; we then explored the use of recombinant chaperone proteins as well-characterized agents to predict antibody nonspecificity...
July 26, 2017: MAbs
https://www.readbyqxmd.com/read/28737444/evolving-patterns-in-a-collaboration-network-of-global-r-d-on-monoclonal-antibodies
#11
Xiangjun Kong, Jian-Bo Wan, Hao Hu, Shibing Su, Yuanjia Hu
We investigated the evolution process of collaborative inter-organizational network of the research and development (R&D) on monoclonal antibody (mAb) over the past 30 years. The annual detection of the collaboration network provides dynamics on network structures and relationship changes among different organizations. Our research showed continuous growth of the network's scale and complexity due to the constant entry of new organizations and the forging of new partnering relationships. The evolving topological features reveal a core-periphery structure that became clearer over time and an increasing heterogeneity within the collaborative mAb R&D network...
July 24, 2017: MAbs
https://www.readbyqxmd.com/read/28726542/generation-and-functional-characterization-of-anti-human-and-anti-mouse-il-36r-antagonist-monoclonal-antibodies
#12
Rajkumar Ganesan, Ernest L Raymond, Detlev Mennerich, Joseph R Woska, Gary Caviness, Christine Grimaldi, Jennifer Ahlberg, Rocio Perez, Simon Roberts, Danlin Yang, Kavita Jerath, Kristopher Truncali, Lee Frego, Eliud Sepulveda, Priyanka Gupta, Su-Ellen Brown, Michael D Howell, Keith A Canada, Rachel Kroe-Barrett, Jay S Fine, Sanjaya Singh, M Lamine Mbow
Deficiency of interleukin (IL)-36 receptor antagonist (DITRA) syndrome is a rare autosomal recessive disease caused by mutations in IL36RN. IL-36R is a cell surface receptor and a member of the IL1R family that is involved in inflammatory responses triggered in skin and other epithelial tissues. Accumulating evidence suggests that IL-36R signaling may play a role in the pathogenesis of psoriasis. Therapeutic intervention of IL-36R signaling offers an innovative treatment paradigm for targeting epithelial cell-mediated inflammatory diseases such as the life-threatening psoriasis variant called generalized pustular psoriasis (GPP)...
July 20, 2017: MAbs
https://www.readbyqxmd.com/read/28708446/elisa-reagent-coverage-evaluation-by-affinity-purification-tandem-mass-spectrometry
#13
Scott M Henry, Elissa Sutlief, Oscar Salas-Solano, John Valliere-Douglass
Host cell proteins (HCPs) must be adequately removed from recombinant therapeutics by downstream processing to ensure patient safety, product quality, and regulatory compliance. HCP process clearance is typically monitored by enzyme-linked immunosorbent assay (ELISA) using a polyclonal reagent. Recently, mass spectrometry (MS) has been utilized to identify specific HCP process impurities and monitor their clearance. Despite this capability, ELISA remains the preferred analytical approach due to its simplicity and throughput...
July 14, 2017: MAbs
https://www.readbyqxmd.com/read/28692328/fabs-in-tandem-immunoglobulin-is-a-novel-and-versatile-bispecific-design-for-engaging-multiple-therapeutic-targets
#14
Shiyong Gong, Fang Ren, Danqing Wu, Xuan Wu, Chengbin Wu
In recent years, the development of bispecific antibody (bsAb) has become a major trend in the biopharmaceutical industry. By simultaneously engaging two molecular targets, bsAbs show unique mechanisms of action that could lead to clinical benefits unattainable by conventional monoclonal antibodies. Various bsAb generation formats have been described, and several are being investigated in clinical development. However, some bsAb constructs have proven to be problematic due to their unfavorable physicochemical and pharmacokinetic properties, as well as poor manufacturing efficiencies...
July 10, 2017: MAbs
https://www.readbyqxmd.com/read/28682148/pharmacokinetics-of-an-intracerebroventricularly-administered-antibody-in-rats
#15
Yuki Noguchi, Motohiro Kato, Kazuhisa Ozeki, Masaki Ishigai
The pharmacokinetics (PK) of an antibody in the brain and the spinal cord is insufficiently understood, which is an obstacle to the discovery of antibody drugs that target diseases in the central nervous system. In this study, we focused on the elimination of IgG from cerebrospinal fluid (CSF) circulating in the brain and the spinal cord in rats, and, to evaluate the influence of CSF bulk flow on the clearance of IgG, also examined the PK of inulin in CSF. To monitor their concentrations in CSF, IgG and inulin were co-administered into the lateral ventricle via a catheter, and CSF was collected from the cisterna magna via another catheter time-sequentially...
July 6, 2017: MAbs
https://www.readbyqxmd.com/read/28617076/characterization-of-highly-concentrated-antibody-solution-a-toolbox-for-the-description-of-protein-long-term-solution-stability
#16
Marie-Therese Schermeyer, Anna K Wöll, Bas Kokke, Michel Eppink, Jürgen Hubbuch
High protein titers are gaining importance in biopharmaceutical industry. A major challenge in the development of highly concentrated mAb solutions is their long-term stability and often incalculable viscosity. The complexity of the molecule itself, as well as the various molecular interactions, make it difficult to describe their solution behavior. To study the formulation stability, long- and short-range interactions and the formation of complex network structures have to be taken into account. For a better understanding of highly concentrated solutions, we combined established and novel analytical tools to characterize the effect of solution properties on the stability of highly concentrated mAb formulations...
June 15, 2017: MAbs
https://www.readbyqxmd.com/read/28581886/enhanced-immunization-techniques-to-obtain-highly-specific-monoclonal-antibodies
#17
Rodrigo de Almeida, Cecília Naomi Nakamura, Marina de Lima Fontes, Elenice Deffune, Sérgio Luis Felisbino, Ramon Kaneno, Wagner José Fávaro, Athanase Billis, Marcel Otávio Cerri, Ana Marisa Fusco-Almeida, Maria José Mendes-Giannini, Andrei Moroz
Despite fast advances in genomics and proteomics, monoclonal antibodies (mAbs) are still a valuable tool for areas such as the evolution of basic research in stem cells and cancer, for immunophenotyping cell populations, diagnosing and prognosis of diseases, and for immunotherapy. To summarize different subtractive immunization approaches successfully employed for the production of highly specific antibodies, we identified scientific articles in NCBI PubMed using the following search terms: subtractive immunization, monoclonal antibody, tolerization, neonatal, high-zone tolerance, masking immunization...
June 5, 2017: MAbs
https://www.readbyqxmd.com/read/28678617/safety-of-biologics-therapy-monoclonal-antibodies-cytokines-fusion-proteins-hormones-enzymes-coagulation-proteins-vaccines-botulinum-toxins
#18
https://www.readbyqxmd.com/read/28657418/chemically-defined-camelid-antibody-bioconjugate-for-the-magnetic-resonance-imaging-of-alzheimer-s-disease
#19
Matthias Vandesquille, Tengfei Li, Chrystelle Po, Christelle Ganneau, Pascal Lenormand, Clémence Dudeffant, Christian Czech, Fiona Grueninger, Charles Duyckaerts, Benoît Delatour, Marc Dhenain, Pierre Lafaye, Sylvie Bay
Today, molecular imaging of neurodegenerative diseases is mainly based on small molecule probes. Alternatively, antibodies are versatile tools that may be developed as new imaging agents. Indeed, they can be readily obtained to specifically target any antigen of interest and their scaffold can be functionalized. One of the critical issues involved in translating antibody-based probes to the clinic is the design and synthesis of perfectly-defined conjugates. Camelid single-domain antibody-fragments (VHHs) are very small and stable antibodies that are able to diffuse in tissues and potentially cross the blood brain barrier (BBB)...
August 2017: MAbs
https://www.readbyqxmd.com/read/28640663/glycosylation-profile-and-biological-activity-of-remicade%C3%A2-compared-with-flixabi%C3%A2-and-remsima%C3%A2
#20
Changsoo Lee, Min Jeong, JongAh Joanne Lee, Saebom Seo, Sung Chun Cho, Wei Zhang, Orlando Jaquez
As biosimilars enter the market, comparisons of product quality are needed. Manufacturing differences may lead to differences in critical quality attributes, which affect efficacy. Therefore, critical quality attributes (structure and biological activity) of Remicade® and of 2 biosimilar products (Flixabi®/Renflexis® and Remsima®/Inflectra®) were determined. We assessed binding to tumor necrosis factor in a fluorescence competitive binding assay; potency in a luciferase reporter gene assay; percentages of galactosylated glycan, afucose plus high mannosylated glycans, and charged glycan; FcγRIIIa (CD16) binding (assessed by 3 methods); and antibody-dependent cell-mediated cytotoxicity (ADCC) in the NK92-CD16a cell line and in peripheral blood mononuclear cells (PBMC)...
August 2017: MAbs
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