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https://www.readbyqxmd.com/read/29436927/quantitative-analysis-of-glycation-and-its-impact-on-antigen-binding
#1
Jingjie Mo, Renzhe Jin, Qingrong Yan, Izabela Sokolowska, Michael J Lewis, Ping Hu
Glycation has been observed in antibody therapeutics manufactured by the fed-batch fermentation process. It not only increases the heterogeneity of antibodies, but also potentially affects product safety and efficacy. In this study, non-glycated and glycated fractions enriched from a monoclonal antibody (mAb1) as well as glucose-stressed mAb1 were characterized using a variety of biochemical, biophysical and biological assays to determine the effects of glycation on the structure and function of mAb1. Glycation was detected at multiple lysine residues and reduced the antigen binding activity of mAb1...
February 13, 2018: MAbs
https://www.readbyqxmd.com/read/29436901/an-anti-tl1a-antibody-for-the-treatment-of-asthma-and-inflammatory-bowel-disease
#2
Adam W Clarke, Lynn Poulton, Doris Shim, David Mabon, Danyal Butt, Matthew Pollard, Vanya Pande, Jean Husten, Jacquelyn Lyons, Chen Tian, Anthony G Doyle
TL1A is an attractive therapeutic target for the treatment of mucosal inflammation associated with inflammatory bowel disease (IBD) and asthma. Blockade of the TL1A pathway has been shown to reduce inflammatory responses while leaving baseline immunity intact, and to be beneficial in animal models of colitis and asthma. Given the therapeutic potential of blocking this pathway in IBD and asthma, we developed C03V, a human antibody that binds with high affinity to soluble and membrane-bound TL1A. In an assay measuring apoptosis induced by exogenous TL1A, C03V was 43-fold more potent than the next most potent anti-TL1A antibody analyzed...
February 13, 2018: MAbs
https://www.readbyqxmd.com/read/29436897/influence-of-disulfide-bond-isoforms-on-drug-conjugation-sites-in-cysteine-linked-igg2-antibody-drug-conjugates
#3
Lily Liu-Shin, Adam Fung, Arun Malhotra, Gayathri Ratnaswamy
Cysteine-linked antibody-drug conjugates (ADCs) produced from IgG2 monoclonal antibodies (mAbs) are more heterogeneous than ADCs generated from IgG1 mAbs, as IgG2 ADCs are composed of a wider distribution of molecules, typically containing 0 - 12 drug-linkers per antibody. The three disulfide isoforms (A, A/B, and B) of IgG2 antibodies confer differences in solvent accessibilities of the interchain disulfides and contribute to the structural heterogeneity of cysteine-linked ADCs. ADCs derived from either IgG2-A or IgG2-B mAbs were compared to better understand the role of disulfide isoforms on attachment sites and distribution of conjugated species...
February 13, 2018: MAbs
https://www.readbyqxmd.com/read/29425077/the-nistmab-tryptic-peptide-spectral-library-for-monoclonal-antibody-characterization
#4
Qian Dong, Yuxue Liang, Xinjian Yan, Sanford P Markey, Yuri A Mirokhin, Dmitrii V Tchekhovskoi, Tallat H Bukhari, Stephen E Stein
We describe the creation of a mass spectral library composed of all identifiable spectra derived from the tryptic digest of the NISTmAb IgG1κ. The library is a unique reference spectral collection developed from over six million peptide-spectrum matches acquired by liquid chromatography-mass spectrometry (LC-MS) over a wide range of collision energy. Conventional one-dimensional (1D) LC-MS was used for various digestion conditions and 20- and 24-fraction two-dimensional (2D) LC-MS studies permitted in-depth analyses of single digests...
February 9, 2018: MAbs
https://www.readbyqxmd.com/read/29400603/a-novel-bicistronic-gene-design-couples-stable-cell-line-selection-with-a-fucose-switch-in-a-designer-cho-host-to-produce-native-and-afucosylated-glycoform-antibodies
#5
Gargi Roy, Tom Martin, Arnita Barnes, Jihong Wang, Rod Brian Jimenez, Megan Rice, Lina Li, Hui Feng, Shu Zhang, Raghothama Chaerkady, Herren Wu, Marcello Marelli, Diane Hatton, Jie Zhu, Michael A Bowen
The conserved glycosylation site Asn297 of a monoclonal antibody (mAb) can be decorated with a variety of sugars that can alter mAb pharmacokinetics and recruitment of effector proteins. Antibodies lacking the core fucose at Asn297 (afucosylated mAbs) show enhanced antibody-dependent cell-mediated cytotoxicity (ADCC) and increased efficacy. Here, we describe the development of a robust platform for the manufacture of afucosylated therapeutic mAbs by engineering a Chinese hamster ovary (CHO) host cell line to co-express a mAb with GDP-6-deoxy-D-lyxo-4-hexulose reductase (RMD), a prokaryotic enzyme that deflects an intermediate in the de novo synthesis of fucose to a dead-end product, resulting in the production of afucosylated mAb (GlymaxX™ Technology, ProBioGen)...
February 5, 2018: MAbs
https://www.readbyqxmd.com/read/29393747/practical-approaches-for-overcoming-challenges-in-heightened-characterization-of-antibody-drug-conjugates-with-new-methodologies-and-ultrahigh-resolution-mass-spectrometry
#6
Olga V Friese, Jacquelynn N Smith, Paul W Brown, Jason C Rouse
Antibody-drug conjugation strategies are continuously evolving as researchers work to improve the safety and efficacy of the molecules. However, as a part of process and product development, confirmation of the resulting innovative structures requires new, specialized mass spectrometry (MS) approaches and methods, as compared to those already established for antibody-drug conjugates (ADCs) and the heightened characterization practices used for monoclonal antibodies (mAbs), in order to accurately elucidate the resulting conjugate forms, which can sometimes have labile chemical bonds and more extreme chemical properties like hydrophobic patches...
February 2, 2018: MAbs
https://www.readbyqxmd.com/read/29388872/improving-titer-while-maintaining-quality-of-final-formulated-drug-substance-via-optimization-of-cho-cell-culture-conditions-in-low-iron-chemically-defined-media
#7
Jianlin Xu, Matthew S Rehmann, Xuankuo Xu, Chao Huang, Jun Tian, Nan-Xin Qian, Zheng Jian Li
During biopharmaceutical process development, it is important to improve titer to reduce drug manufacturing costs and to deliver comparable quality attributes of therapeutic proteins, which helps to ensure patient safety and efficacy. We previously reported that relative high-iron concentrations in media increased titer, but caused unacceptable coloration of a fusion protein during early-phase process development. Ultimately, the fusion protein with acceptable color was manufactured using low-iron media, but the titer decreased significantly in the low-iron process...
February 1, 2018: MAbs
https://www.readbyqxmd.com/read/29381421/mild-hypothermic-culture-conditions-affect-residual-host-cell-protein-composition-post-protein-a-chromatography
#8
Cher Hui Goey, David Bell, Cleo Kontoravdi
Host cell proteins (HCPs) are endogenous impurities, and their proteolytic and binding properties can compromise the integrity, and, hence, the stability and efficacy of recombinant therapeutic proteins such as monoclonal antibodies (mAbs). Nonetheless, purification of mAbs currently presents a challenge because they often co-elute with certain HCP species during the capture step of protein A affinity chromatography. A Quality-by-Design (QbD) strategy to overcome this challenge involves identifying residual HCPs and tracing their source to the harvested cell culture fluid (HCCF) and the corresponding cell culture operating parameters...
January 30, 2018: MAbs
https://www.readbyqxmd.com/read/29376776/a-natively-paired-antibody-library-yields-drug-leads-with-higher-sensitivity-and-specificity-than-a-randomly-paired-antibody-library
#9
Adam S Adler, Daniel Bedinger, Matthew S Adams, Michael A Asensio, Robert C Edgar, Renee Leong, Jackson Leong, Rena A Mizrahi, Matthew J Spindler, Srinivasa Rao Bandi, Haichun Huang, Pallavi Tawde, Peter Brams, David S Johnson
Deep sequencing and single-chain variable fragment (scFv) yeast display methods are becoming more popular for discovery of therapeutic antibody candidates in mouse B cell repertoires. In this study, we compare a deep sequencing and scFv display method that retains native heavy and light chain pairing with a related method that randomly pairs heavy and light chain. We performed the studies in a humanized mouse, using interleukin 21 receptor (IL-21R) as a test immunogen. We identified 44 high-affinity binder scFv with the native pairing method and 100 high-affinity binder scFv with the random pairing method...
January 29, 2018: MAbs
https://www.readbyqxmd.com/read/29359992/fc%C3%AE-rii-binding-centyrins-mediate-agonism-and-antibody-dependent-cellular-phagocytosis-when-fused-to-an-anti-ox40-antibody
#10
Di Zhang, Brian Whitaker, Mehabaw G Derebe, Mark L Chiu
Immunostimulatory antibodies against the tumor necrosis factor receptors (TNFR) are emerging as promising cancer immunotherapies. The agonism activity of such antibodies depends on crosslinking to Fc gamma RIIB receptor (FcγRIIB) to enable the antibody multimerization that drives TNFR activation. Previously, Fc engineering was used to enhance the binding of such antibodies to Fcγ receptors. Here, we report the identification of Centyrins as alternative scaffold proteins with binding affinities to homologous FcγRIIB and FcγRIIA, but not to other types of Fcγ receptors...
January 23, 2018: MAbs
https://www.readbyqxmd.com/read/29336721/using-hydrogen-peroxide-to-prevent-antibody-disulfide-bond-reduction-during-manufacturing-process
#11
Cheng Du, Yunping Huang, Ameya Borwankar, Zhijun Tan, Anthony Cura, Joon Chong Yee, Nripen Singh, Richard Ludwig, Michael Borys, Sanchayita Ghose, Nesredin Mussa, Zheng Jian Li
During large-scale monoclonal antibody manufacturing, disulfide bond reduction of antibodies, which results in generation of low molecule weight species, is occasionally observed. When this happens, the drug substance does not meet specifications. Many investigations have been conducted across the biopharmaceutical industry to identify the root causes, and multiple strategies have been proposed to mitigate the problem. The reduction is correlated with the release of cellular reducing components and depletion of dissolved oxygen before, during, and after harvest...
January 16, 2018: MAbs
https://www.readbyqxmd.com/read/29333938/structure-based-engineering-to-restore-high-affinity-binding-of-an-isoform-selective-anti-tgf%C3%AE-1-antibody
#12
Dana M Lord, Julie J Bird, Denise M Honey, Annie Best, Anna Park, Ronnie R Wei, Huawei Qiu
Metelimumab (CAT192) is a human IgG4 monoclonal antibody developed as a TGFβ1-specific antagonist. It was tested in clinical trials for the treatment of scleroderma but later terminated due to lack of efficacy. Subsequent characterization of CAT192 indicated that its TGFβ1 binding affinity was reduced by ∼50-fold upon conversion from the parental single-chain variable fragment (scFv) to IgG4. We hypothesized this result was due to decreased conformational flexibility of the IgG that could be altered via engineering...
January 15, 2018: MAbs
https://www.readbyqxmd.com/read/29313446/monoclonal-antibody-higher-order-structure-analysis-by-high-throughput-protein-conformational-array
#13
Yuanli Song, Deqiang Yu, Mukesh Mayani, Nesredin Mussa, Zheng Jian Li
The elucidation of antibody higher order structure (HOS) is critical in therapeutic antibody development. Since HOS determines the protein bioactivity and chemo-physical properties, this knowledge can help to ensure that the safety and efficacy attributes are not compromised. Protein conformational array (PCA) is a novel method for determining the HOS of monoclonal antibodies. Previously, we successfully utilized an enzyme-linked immunosorbent assay (ELISA)-based PCA along with other bioanalytical tools to elucidate the structures of antibody aggregates...
January 9, 2018: MAbs
https://www.readbyqxmd.com/read/29309213/development-and-characterization-of-an-anti-rituximab-monoclonal-antibody-panel
#14
Minoru Tada, Takuo Suzuki, Akiko Ishii-Watabe
During the development of monoclonal antibodies (mAbs) and other therapeutic proteins, immunogenicity, in particular the induction of anti-drug antibodies (ADAs), is an important concern, and thus immunogenicity assessment is a requirement for their approval. Establishment of appropriate methods for detecting and characterizing ADAs is necessary for immunogenicity assessment, but the lack of commonly available reference standards makes it difficult to compare and evaluate the methods. It is also difficult to compare the data with those obtained by other methods or facilities without reference standards...
January 8, 2018: MAbs
https://www.readbyqxmd.com/read/29300693/antibodies-to-watch-in-2018
#15
Hélène Kaplon, Janice M Reichert
The pace of antibody therapeutics development accelerated in 2017, and this faster pace is projected to continue through 2018. Notably, the annual number of antibody therapeutics granted a first approval in either the European Union (EU) or United States (US) reached double-digits (total of 10) for the first time in 2017. The 10 antibodies granted approvals are: brodalumab, dupilumab, sarilumab, guselkumab, benralizumab, ocrelizumab, inotuzumab ozogamicin, avelumab, duvalumab, and emicizumab. Brodalumab, however, had already been approved in Japan in 2016...
January 4, 2018: MAbs
https://www.readbyqxmd.com/read/29293399/challenges-and-new-frontiers-in-analytical-characterization-of-antibody-drug-conjugates
#16
Anil Wagh, Hangtian Song, Ming Zeng, Li Tao, Tapan K Das
Antibody-drug conjugates (ADCs) are a growing class of biotherapeutics in which a potent small molecule is linked to an antibody. ADCs are highly complex and structurally heterogeneous, typically containing numerous product-related species. One of the most impactful steps in ADC development is the identification of critical quality attributes to determine product characteristics that may affect safety and efficacy. However, due to the additional complexity of ADCs relative to the parent antibodies, establishing a solid understanding of the major quality attributes and determining their criticality are a major undertaking in ADC development...
January 2, 2018: MAbs
https://www.readbyqxmd.com/read/29283291/structural-insights-into-humanization-of-anti-tissue-factor-antibody-10h10
#17
Alexey Teplyakov, Galina Obmolova, Thomas J Malia, Gopalan Raghunathan, Christian Martinez, Johan Fransson, Wilson Edwards, Judith Connor, Matthew Husovsky, Heena Beck, Ellen Chi, Sandra Fenton, Hong Zhou, Juan Carlos Almagro, Gary L Gilliland
Murine antibody 10H10 raised against human tissue factor is unique in that it blocks the signaling pathway, and thus inhibits angiogenesis and tumor growth without interfering with coagulation. As a potential therapeutic, the antibody was humanized in a two-step procedure. Antigen-binding loops were grafted onto selected human frameworks and the resulting chimeric antibody was subjected to affinity maturation by using phage display libraries. The results of humanization were analyzed from the structural perspective through comparison of the structure of a humanized variant with the parental mouse antibody...
December 28, 2017: MAbs
https://www.readbyqxmd.com/read/29271699/establishing-in-vitro-in-vivo-correlations-to-screen-monoclonal-antibodies-for-physicochemical-properties-related-to-favorable-human-pharmacokinetics
#18
Lindsay B Avery, Jason Wade, Mengmeng Wang, Amy Tam, Amy King, Nicole Piche-Nicholas, Mania S Kavosi, Steve Penn, David Cirelli, Jeffrey C Kurz, Minlei Zhang, Orla Cunningham, Rhys Jones, Brian J Fennell, Barry McDonnell, Paul Sakorafas, James Apgar, William J Finlay, Laura Lin, Laird Bloom, Denise M O'Hara
Implementation of in vitro assays that correlate with in vivo human pharmacokinetics (PK) would provide desirable preclinical tools for the early selection of therapeutic monoclonal antibody (mAb) candidates with minimal non-target-related PK risk. Use of these tools minimizes the likelihood that mAbs with unfavorable PK would be advanced into costly preclinical and clinical development. In total, 42 mAbs varying in isotype and soluble versus membrane targets were tested in in vitro and in vivo studies. MAb physicochemical properties were assessed by measuring non-specific interactions (DNA- and insulin-binding ELISA), self-association (affinity-capture self-interaction nanoparticle spectroscopy) and binding to matrix-immobilized human FcRn (surface plasmon resonance and column chromatography)...
December 22, 2017: MAbs
https://www.readbyqxmd.com/read/29271693/integrated-flow-through-purification-for-therapeutic-monoclonal-antibodies-processing
#19
Takamitsu Ichihara, Takao Ito, Yasuhiko Kurisu, Kevin Galipeau, Christopher Gillespie
An integrated all flow-through technology platform for the purification of therapeutic monoclonal antibodies (mAb), consisting of activated carbon and flow-through cation and anion exchange chromatography steps, can replace a conventional chromatography platform. This new platform was observed to have excellent impurity clearance at high mAb loadings with overall mAb yield exceeding 80%. Robust removal of DNA and host cell protein was demonstrated by activated carbon and a new flow-through cation exchange resin exhibited excellent clearance of mAb aggregate with high monomer recoveries...
December 22, 2017: MAbs
https://www.readbyqxmd.com/read/29239690/antibody-drug-conjugates-design-and-development-for-therapy-and-imaging-in-and-beyond-cancer-labex-mabimprove-industrial-workshop-july-27-28-2017-tours-france
#20
Camille Martin, Claire Kizlik-Masson, André Pèlegrin, Hervé Watier, Marie-Claude Viaud-Massuard, Nicolas Joubert
The annual "Antibody Industrial Symposium", co organized by LabEx MAbImprove, MabDesign and Polepharma, was held in Tours, France on June 27-28, 2017. The focus was on antibody-drug-conjugates (ADCs), new entities which realize the hope of Paul Ehrlich's magic bullet. ADCs result from the bioconjugation of a highly cytotoxic drug to a selective monoclonal antibody, which acts as a vector. Building on knowledge gained during the development of three approved ADCs, brentuximab vedotin (Adcetris®), ado trastuzumab emtansine (Kadcyla®) and inotuzumab ozogamicin (Besponsa®), and the many ADCs in development, this meeting addressed strategies and the latest innovations in the field from fundamental research to manufacturing...
December 14, 2017: MAbs
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