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November 13, 2018: MAbs
Clive Metcalfe, Thomas Dougall, Chris Bird, Peter Rigsby, Marie-Emmanuelle Behr-Gross, Meenu Wadhwa, Participants Of The Study
Due to the increase in the number of infliximab products, the need for global harmonization of the bioactivity of this monoclonal antibody was recognized by the World Health Organization (WHO). In response, the National Institute for Biological Standards and Control (NIBSC) developed the first international standard (IS) for infliximab, which targets tumour necrosis factor (TNF). Each ampoule is assigned values of 500 IU of TNF neutralizing activity and 500 IU of binding activity. Two preparations of infliximab were formulated and lyophilized at NIBSC prior to evaluation in a collaborative study for their suitability to serve as an IS for the in vitro biological activity of infliximab...
November 5, 2018: MAbs
Wei-Ying Kuo, Hung-Ju Hsu, Chun-Yi Wu, Hong-Sen Chen, Yu-Chi Chou, Yueh-Liang Tsou, Hung-Pin Peng, Jhih-Wei Jian, Chung-Ming Yu, Yi-Kai Chiu, Ing-Chien Chen, Chao-Ping Tung, Michael Hsiao, Chia-Lung Lin, Yong Alison Wang, Andrew H-J Wang, An-Suei Yang
HER2-ECD (human epidermal growth factor receptor 2 - extracellular domain) is a prominent therapeutic target validated for treating HER2-positive breast and gastric cancer, but HER2-specific therapeutic options for treating advanced gastric cancer remain limited. We have developed antibody-drug conjugates (ADCs), comprising IgG1 linked via valine-citrulline to monomethyl auristatin E, with potential to treat HER2-positive gastric cancer in humans. The antibodies optimally selected from the ADC discovery platform, which was developed to discover antibody candidates suitable for immunoconjugates from synthetic antibody libraries designed using antibody-antigen interaction principles, were demonstrated to be superior immunoconjugate targeting modules in terms of efficacy and off-target toxicity...
October 26, 2018: MAbs
Douglas S Rehder, Chris J Wisniewski, Denfeng Liu, Diya Ren, Dell Farnan, Matthew R Schenauer
While characterizing a therapeutic IgG4 monoclonal antibody (mAb), we observed a variant with a mass 1177 Da larger than the predominant mAb form that could not be ascribed to previously described modifications. Through successive rounds of experimentation, we localized the mass addition to the C-terminus of the heavy chain (HC). During this process we observed that when the mAb was broken down into separate domains, the Fc and the 1177 Da-modified Fc could be chromatographically separated. Separation allowed collection of native and modified Fc fractions for LC/MS peptide mapping...
October 26, 2018: MAbs
T Jennifer Lin, Kathryn M Beal, Paul W Brown, Heather S DeGruttola, Mellisa Ly, Wenge Wang, Chia H Chu, Robert L Dufield, Gerald F Casperson, James A Carroll, Olga V Friese, Bruno Figueroa, Lisa A Marzilli, Karin Anderson, Jason C Rouse
Amino acid sequence variation in protein therapeutics requires close monitoring during cell line and cell culture process development. A cross-functional team of Pfizer colleagues from the Analytical and Bioprocess Development departments worked closely together for over 6 years to formulate and communicate a practical, reliable sequence variant (SV) testing strategy with state-of-the-art techniques that did not necessitate more resources or lengthen project timelines. The final Pfizer SV screening strategy relies on next-generation sequencing (NGS) and amino acid analysis (AAA) as frontline techniques to identify mammalian cell clones with genetic mutations and recognize cell culture process media/feed conditions that induce misincorporations, respectively...
October 25, 2018: MAbs
Aaron O Bailey, Guanghui Han, Wilson Phung, Paul Gazis, Jennifer Sutton, Jonathan L Josephs, Wendy Sandoval
The preponderance and diversity of charge variants in therapeutic monoclonal antibodies has implications for antibody efficacy and degradation. Understanding the extent and impact of minor antibody variants is of great interest, and it is also a critical regulatory requirement. Traditionally, a combination of approaches is used to characterize antibody charge heterogeneity, including ion exchange chromatography and independent mass spectrometric variant site mapping after proteolytic digestion. Here, we describe charge variant native mass spectrometry (CVMS), an integrated native ion exchange mass spectrometry-based charge variant analytical approach that delivers detailed molecular information in a single, semi-automated analysis...
October 19, 2018: MAbs
Lily Pei-Yao Liu-Shin, Adam Fung, Arun Malhotra, Gayathri Ratnaswamy
Antibody-drug conjugates (ADCs) that are formed using thiol-maleimide chemistry are commonly produced by reactions that occur at or above neutral pHs. Alkaline environments can promote disulfide bond scrambling, and may result in the reconfiguration of interchain disulfide bonds in IgG antibodies, particularly in the IgG2 and IgG4 subclasses. IgG2-A and IgG2-B antibodies generated under basic conditions yielded ADCs with comparable average drug-to-antibody ratios and conjugate distributions. In contrast, the antibody disulfide configuration affected the distribution of ADCs generated under acidic conditions...
October 19, 2018: MAbs
T Noelle Lombana, Marissa L Matsumoto, Jack Bevers Iii, Amy M Berkley, Evangeline Toy, Ryan Cook, Yutian Gan, Changchun Du, Peter Liu, Paul Schnier, Wendy Sandoval, Zhengmao Ye, Jill M Schartner, Jeong Kim, Christoph Spiess
As an immune evasion strategy, MICA and MICB, the major histocompatibility complex class I homologs, are proteolytically cleaved from the surface of cancer cells leading to impairment of CD8 + T cell- and natural killer cell-mediated immune responses. Antibodies that inhibit MICA/B shedding from tumors have therapeutic potential, but the optimal epitopes are unknown. Therefore, we developed a high-resolution, high-throughput glycosylation-engineered epitope mapping (GEM) method, which utilizes site-specific insertion of N-linked glycans onto the antigen surface to mask local regions...
October 11, 2018: MAbs
Florian Füssl, Anne Trappe, Ken Cook, Kai Scheffler, Oliver Fitzgerald, Jonathan Bones
Charge variant analysis is a widely used tool to monitor changes in product quality during the manufacturing process of monoclonal antibodies (mAbs). Although it is a powerful technique for revealing mAb heterogeneity, an unexpected outcome, for example the appearance of previously undetected isoforms, requires further, time-consuming analysis. The process of identifying these unknowns can also result in unwanted changes to the molecule that are not attributable to the manufacturing process. To overcome this, we recently reported a method combining highly selective cation exchange chromatography-based charge variant analysis with on-line mass spectrometric (MS) detection...
October 8, 2018: MAbs
Nayoung Lee, JongAh Joanne Lee, Hahymn Yang, Serim Baek, Soohwan Kim, Sooshin Kim, Tongkeun Lee, Dami Song, Gwangmin Park
Biosimilars are biologic products that are highly similar to a licensed reference product in terms of quality, safety, and efficacy. SB5 is a biosimilar of Humira® (adalimumab) developed by Samsung Bioepis. To demonstrate its biosimilarity in quality to Humira®, we performed a comprehensive characterization in terms of structure, physicochemical properties, and biological properties following the International Conference on Harmonization, US Food and Drug Administration, and European Medicines Agency guidelines...
October 8, 2018: MAbs
Jun Zhao, Ruth Nussinov, Buyong Ma
A key question in immunology is whether antigen recognition and Fc receptor (FcR) binding are allosterically linked. This question is also relevant for therapeutic antibody design. Antibody Fab and Fc domains are connected by flexible unstructured hinge region. Fc chains have conserved glycosylation sites at Asn297, with each conjugated to a core heptasaccharide and forming biantennary Fc glycan. The glycans modulate the Fc conformations and functions. It is well known that the antibody Fab and Fc domains and glycan affect antibody activity, but whether these elements act independently or synergistically is still uncertain...
October 5, 2018: MAbs
Anja Resemann, Lily Liu-Shin, Guillaume Tremintin, Arun Malhotra, Adam Fung, Fang Wang, Gayathri Ratnaswamy, Detlev Suckau
Human antibodies of the IgG2 subclass exhibit complex inter-chain disulfide bonding patterns that result in three structures, namely A, A/B, and B. In therapeutic applications, the distribution of disulfide isoforms is a critical product quality attribute because each configuration affects higher order structure, stability, isoelectric point, and antigen binding. The current standard for quantification of IgG2 disulfide isoform distribution is based on chromatographic or electrophoretic techniques that require additional characterization using mass spectrometry (MS)-based methods to confirm disulfide linkages...
October 2, 2018: MAbs
Betty C B Huang, Yun Cheol Kim, Stefanie Bañas, Robyn M Barfield, Penelope M Drake, Igor Rupniewski, William E Haskins, David Rabuka
The advantages of site-specific over stochastic bioconjugation technologies include homogeneity of product, minimal perturbation of protein structure/function, and - increasingly - the ability to perform structure activity relationship studies at the conjugate level. When selecting the optimal location for site-specific payload placement, many researchers turn to in silico modeling of protein structure to identify regions predicted to offer solvent-exposed conjugatable sites while conserving protein function...
September 25, 2018: MAbs
Kannan Sankar, Kam Hon Hoi, Yizhou Yin, Prasanna Ramachandran, Nisana Andersen, Amy Hilderbrand, Paul McDonald, Christoph Spiess, Qing Zhang
Monoclonal antibodies (mAbs) have become a major class of protein therapeutics that target a spectrum of diseases ranging from cancers to infectious diseases. Similar to any protein molecule, mAbs are susceptible to chemical modifications during the manufacturing process, long-term storage, and in vivo circulation that can impair their potency. One such modification is the oxidation of methionine residues. Chemical modifications that occur in the complementarity-determining regions (CDRs) of mAbs can lead to the abrogation of antigen binding and reduce the drug's potency and efficacy...
September 25, 2018: MAbs
Fabian Richter, Kirstin A Zettlitz, Oliver Seifert, Andreas Herrmann, Peter Scheurich, Klaus Pfizenmaier, Roland E Kontermann
Selective inhibition of tumor necrosis factor (TNF) signaling through the proinflammatory axis of TNF-receptor 1 (TNFR1) while leaving pro-survival and regeneration-promoting signals via TNFR2 unaffected is a promising strategy to circumvent limitations of complete inhibition of TNF action by the approved anti-TNF drugs. A previously developed humanized antagonistic TNFR1-specific antibody, ATROSAB, showed potent inhibition of TNFR1-mediated cellular responses. Because the parental mouse antibody H398 possesses even stronger inhibitory potential, we scrutinized the specific binding parameters of the two molecules and revealed a faster dissociation of ATROSAB compared to H398...
September 25, 2018: MAbs
Sven Loebrich, Elisa Clark, Kristina Ladd, Stefani Takahashi, Anna Brousseau, Seth Kitchener, Robert Herbst, Thomas Ryll
The extent and pattern of glycosylation on therapeutic antibodies can influence their circulatory half-life, engagement of effector functions, and immunogenicity, with direct consequences to efficacy and patient safety. Hence, controlling glycosylation patterns is central to any drug development program, yet poses a formidable challenge to the bio-manufacturing industry. Process changes, which can affect glycosylation patterns, range from manufacturing at different scales or sites, to switching production process mode, all the way to using alternative host cell lines...
September 25, 2018: MAbs
Zvezdan Pavlovic, Jarrett J Adams, Levi L Blazer, Amandeep K Gakhal, Nick Jarvik, Zachary Steinhart, Mélanie Robitaille, Keith Mascall, James Pan, Stephane Angers, Jason Moffat, Sachdev S Sidhu
Secreted Wnt ligands play a major role in the development and progression of many cancers by modulating signaling through cell-surface Frizzled receptors (FZDs). In order to achieve maximal effect on Wnt signaling by targeting the cell surface, we developed a synthetic antibody targeting six of the 10 human FZDs. We first identified an anti-FZD antagonist antibody (F2) with a specificity profile matching that of OMP-18R5, a monoclonal antibody that inhibits growth of many cancers by targeting FZD7, FZD1, FZD2, FZD5 and FZD8...
September 25, 2018: MAbs
Heather A Cooke, Joe Arndt, Chao Quan, Renée I Shapiro, Dingyi Wen, Susan Foley, Malgorzata M Vecchi, Martin Preyer
Bispecific antibody therapeutics can expand the functionality of a conventional monoclonal antibody drug because they can bind multiple antigens. However, their great potential is counterbalanced by the challenges faced in their production. The classic asymmetric bispecific containing an Fc requires the expression of four unique chains - two light chains and two heavy chains; each light chain must pair with its correct heavy chain, which then must heterodimerize to form the full bispecific. The light-chain pairing problem has several solutions, some of which require engineering and optimization for each bispecific pair...
September 20, 2018: MAbs
Jianlin Xu, Peifeng Tang, Andrew Yongky, Barry Drew, Michael C Borys, Shijie Liu, Zheng Jian Li
Temperature shift (TS) to a hypothermic condition has been widely used during protein production processes that use Chinese hamster ovary (CHO) cells. The effect of temperature on cell growth, metabolites, protein titer and quality depends on cell line, product, and other bioreactor conditions. Due to the large numbers of experiments, which typically last 2-3 weeks each, limited systematic TS studies have been reported with multiple shift temperatures and steps at different times. Here, we systematically studied the effect of temperature on cell culture performance for the production of two monoclonal antibodies by industrial GS and DG44 CHO cell lines...
September 19, 2018: MAbs
Yutong Jin, Ziqing Lin, Qingge Xu, Cexiong Fu, Zhaorui Zhang, Qunying Zhang, Wayne A Pritts, Ying Ge
The pharmaceutical industry's interest in monoclonal antibodies (mAbs) and their derivatives has spurred rapid growth in the commercial clinical pipeline of these effective therapeutics. The complex micro-heterogeneity of mAbs requires in-depth structural characterization for critical quality attribute assessment and quality assurance. Currently, mass spectrometry (MS)-based methods are the gold standard in mAb analysis, primarily with a bottom-up approach in which immunoglobulins G (IgGs) and their variants are digested into peptides to facilitate the analysis...
September 19, 2018: MAbs
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