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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
#1
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...
March 27, 2017: MAbs
https://www.readbyqxmd.com/read/28323513/transmembrane-tnf-dependent-uptake-of-anti-tnf-antibodies
#2
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-alpha (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-alpha converting enzyme (TACE) to release the 15 kDa form of soluble TNF (sTNF). TmTNF and sTNF interact with two distinct receptors, TNF-R1 (p55) and TNF-R2 (p75), to mediate the multiple biological 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...
March 21, 2017: MAbs
https://www.readbyqxmd.com/read/28306378/development-of-a-monoclonal-anti-adamts-5-antibody-that-specifically-blocks-the-interaction-with-lrp1
#3
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...
March 17, 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
#4
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 two 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 biological properties by standard or state-of-the-art analytical methods, using multiple lots expiring between March 2015 and December 2019...
March 15, 2017: MAbs
https://www.readbyqxmd.com/read/28287337/generation-and-characterization-of-protective-antibodies-to-marburg-virus
#5
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...
March 13, 2017: MAbs
https://www.readbyqxmd.com/read/28273004/tcr-like-antibody-drug-conjugates-mediate-killing-of-tumor-cells-with-low-peptide-hla-targets
#6
Devin B Lowe, Camille K Bivens, Alexis S Mobley, Christian E Herrera, Amanda L McCormick, Timea Wichner, Manoj K Sabnani, Laurence M Wood, Jon A Weidanz
The currently marketed antibody-drug conjugates (ADC) destabilize microtubule assembly in cancer cells and initiate apoptosis in patients. However, few tumor antigens (TA) are expressed at high densities on cancer lesions, potentially minimizing the therapeutic index of current ADC regimens. The peptide/human leukocyte antigen (HLA) complex can be specifically targeted by therapeutic antibodies (designated T cell receptor [TCR]-like antibodies) and adequately distinguish malignant cells, but has not been the focus of ADC development...
March 8, 2017: MAbs
https://www.readbyqxmd.com/read/28272973/glycation-of-antibodies-modification-methods-and-potential-effects-on-biological-functions
#7
Bingchuan Wei, Kelsey Berning, Cynthia Quan, Yonghua Taylor Zhang
Glycation is an important protein modification that could potentially affect bioactivity and molecular stability, and glycation of therapeutic proteins such as monoclonal antibodies should be well characterized. Glycated protein could undergo further degradation into advance glycation end (AGE) products. Here, we review the root cause of glycation during the manufacturing, storage and in vivo circulation of therapeutic antibodies, and the current analytical methods used to detect and characterize glycation and AGEs, including boronate affinity chromatography, charge-based methods, liquid chromatography-mass spectrometry and colorimetric assay...
March 8, 2017: MAbs
https://www.readbyqxmd.com/read/28346048/mabdelivery-administration-routes-for-antibody-therapy-third-labex-mabimprove-industrial-workshop-july-2-2015-tours-france
#8
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...
February 28, 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
#9
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...
February 23, 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
#10
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...
February 22, 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
#11
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...
February 14, 2017: MAbs
https://www.readbyqxmd.com/read/28281873/resolving-the-micro-heterogeneity-and-structural-integrity-of-monoclonal-antibodies-by-hybrid-mass-spectrometric-approaches
#12
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...
February 14, 2017: MAbs
https://www.readbyqxmd.com/read/28281922/a-high-performance-non-radioactive-potency-assay-for-measuring-cytotoxicity-a-full-substitute-of-the-chromium-release-assay-targeting-the-regulatory-compliance-objective
#13
Alexis Rossignol, Véronique Bonnaudet, Béatrice Clémenceau, Henri Vié, Laurent Bretaudeau
Standardized and biologically relevant potency assays are required by the regulatory authorities for the characterization and quality control of therapeutic antibodies. As critical mechanisms of action (MoA) of antibodies, the antibody-dependent cell-meditated cytotoxicity (ADCC) and complement-dependent cytotoxicity (CDC) must be characterized by appropriate potency assays. The current reference method for measuring cytotoxicity is the (51)Cr-release method. However, radioactivity handling is difficult to implement in an industrial context because of environmental and operator protection constraints...
February 8, 2017: MAbs
https://www.readbyqxmd.com/read/28165915/humanization-of-rabbit-monoclonal-antibodies-via-grafting-combined-kabat-imgt-paratome%C3%A2-complementarity-determining-regions-rationale-and-examples
#14
Yi-Fan Zhang, Mitchell Ho
Rabbit monoclonal antibodies (RabMAbs) can recognize diverse epitopes, including those poorly immunogenic in mice and humans. However, there have been only a few reports on RabMAb humanization, an important antibody engineering step usually done before clinical applications are investigated. To pursue a general method for humanization of RabMAbs, we analyzed the complex structures of five RabMAbs with their antigens currently available in the Protein Data Bank, and identified antigen-contacting residues on the rabbit Fv within the 6 Angstrom distance to its antigen...
February 6, 2017: MAbs
https://www.readbyqxmd.com/read/28136017/the-impact-of-trisulfide-modification-of-antibodies-on-the-properties-of-antibody-drug-conjugates-manufactured-using-thiol-chemistry
#15
Renpeng Liu, Xuan Chen, Junia Dushime, Megan Bogalhas, Alexandru C Lazar, Thomas Ryll, Lintao Wang
Antibody-drug conjugates (ADCs) are promising biotherapeutic agents for the treatment of cancer. The careful monitoring of critical quality attributes is important for ADCs' development, manufacturing and production. In this work, the effect of the presence of a trisulfide bond in the monoclonal antibody (mAb) conjugated to DM4 cytotoxic payload through a disulfide-bond linker sulfo-SPDB (sSPDB) was investigated. Three lots of antibody containing variable levels of trisulfide bonds were used. The identity and levels of trisulfide bonds were determined by liquid chromatography/ mass spectrometry (MS)/MS analysis...
January 31, 2017: MAbs
https://www.readbyqxmd.com/read/28125318/in-silico-prediction-of-concentration-dependent-viscosity-curves-for-monoclonal-antibody-solutions
#16
Dheeraj S Tomar, Li Li, Matthew P Broulidakis, Nicholas G Luksha, Christopher T Burns, Satish K Singh, Sandeep Kumar
Early stage developability assessments of monoclonal antibody (mAb) candidates can help reduce risks and costs associated with their product development. Forecasting viscosity of highly concentrated mAb solutions is an important aspect of such developability assessments. Reliable predictions of concentration-dependent viscosity behaviors for mAb solutions in platform formulations can help screen or optimize drug candidates for flexible manufacturing and drug delivery options. Here, we present a computational method to predict concentration-dependent viscosity curves for mAbs solely from their sequence-structural attributes...
January 26, 2017: MAbs
https://www.readbyqxmd.com/read/28125314/bisfabs-tools-for-rapidly-screening-hybridoma-iggs-for-their-activities-as-bispecific-antibodies
#17
Sanket Patke, Ji Li, Peiyin Wang, Dion Slaga, Jennifer Johnston, Sunil Bhakta, Siler Panowski, Liping L Sun, Teemu Junttila, Justin M Scheer, Diego A Ellerman
Bispecific antibodies are a growing class of therapeutic molecules. Many of the current bispecific formats require DNA engineering to convert the parental monoclonal antibodies into the final bispecific molecules. We describe here a method to generate bispecific molecules from hybridoma IgGs in 3-4 days using chemical conjugation of antigen-binding fragments (Fabs) (bisFabs). Proteolytic digestion conditions for each IgG isotype were analyzed to optimize the yield and quality of the final conjugates. The resulting bisFabs showed no significant amounts of homodimers or aggregates...
January 26, 2017: MAbs
https://www.readbyqxmd.com/read/28106519/subunit-mass-analysis-for-monitoring-antibody-oxidation
#18
Izabela Sokolowska, Jingjie Mo, Jia Dong, Michael J Lewis, Ping Hu
Methionine oxidation is a common posttranslational modification (PTM) of monoclonal antibodies (mAbs). Oxidation can reduce the in-vivo half-life, efficacy and stability of the product. Peptide mapping is commonly used to monitor the levels of oxidation, but this is a relatively time-consuming method. A high-throughput, automated subunit mass analysis method was developed to monitor antibody methionine oxidation. In this method, samples were treated with IdeS, EndoS and dithiothreitol to generate three individual IgG subunits (light chain, Fd' and single chain Fc)...
January 20, 2017: MAbs
https://www.readbyqxmd.com/read/28102754/enhancement-of-antibody-functions-through-fc-multiplications
#19
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
#20
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
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