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Jinsung Noh, Okju Kim, Yushin Jung, Haejun Han, Jung-Eun Kim, Soohyun Kim, Sanghyub Lee, Jaeseong Park, Rae Hyuck Jung, Sang Il Kim, Jaejun Park, Jerome Han, Hyunho Lee, Duck Kyun Yoo, Amos C Lee, Euijin Kwon, Taehoon Ryu, Junho Chung, Sunghoon Kwon
In antibody discovery, in-depth analysis of an antibody library and high-throughput retrieval of clones in the library are crucial to identifying and exploiting rare clones with different properties. However, existing methods have technical limitations, such as low process throughput from the laborious cloning process and waste of the phenotypic screening capacity from unnecessary repetitive tests on the dominant clones. To overcome the limitations, we developed a new high-throughput platform for the identification and retrieval of clones in the library, TrueRepertoire™...
February 8, 2019: MAbs
Antoine Guillon, Jeoffrey Pardessus, Pierre Lhommet, Christelle Parent, Renaud Respaud, Denis Marchand, Jérôme Montharu, Michèle De Monte, Philip Janiak, Christophe Boixel, Héloïse Audat, Sylvain Huille, Etienne Guillot, Nathalie Heuze-Vourc'h
Therapeutic antibodies (Abs) are emerging as major drugs to treat respiratory diseases, and inhalation may provide substantial benefits for their delivery. Understanding the behavior of Abs after pulmonary deposition is critical for their development. We investigated the pharmacokinetics of a nebulized Ab by continuous sampling in lung parenchyma using microdialysis in non-human primates. We defined the optimal conditions for microdialysis of Ab and demonstrated that lung microdialysis of Ab is feasible over a period of several days...
February 4, 2019: MAbs
Nathan D Trinklein, Duy Pham, Ute Schellenberger, Ben Buelow, Andrew Boudreau, Priya Choudhry, Starlynn C Clarke, Kevin Dang, Katherine E Harris, Suhasini Iyer, Brett Jorgensen, Payal P Pratap, Udaya S Rangaswamy, Harshad S Ugamraj, Omid Vafa, Arun P Wiita, Wim Van Schooten, Roland Buelow, Shelley Force Aldred
T cell-recruiting bispecific antibodies (T-BsAbs) have shown potent tumor killing activity in humans, but cytokine release-related toxicities have affected their clinical utility. The use of novel anti-CD3 binding domains with more favorable properties could aid in the creation of T-BsAbs with improved therapeutic windows. Using a sequence-based discovery platform, we identified new anti-CD3 antibodies from humanized rats that bind to multiple epitopes and elicit varying levels of T-cell activation. In T-BsAb format, 12 different anti-CD3 arms induce equivalent levels of tumor cell lysis by primary T cells, but potency varies by a thousand-fold...
January 30, 2019: MAbs
Hans Van der Weken, Eric Cox, Bert Devriendt
To enable large-scale antibody production, the creation of a stable, high producer cell line is essential. This process often takes longer than 6 months using standard limited dilution techniques and is very labor intensive. The use of a tri-cistronic vector expressing green fluorescent protein (GFP) and both antibody chains, separated by a GT2A peptide sequence, allows expression of all proteins under a single promotor in equimolar ratios. By combining the advantages of 2A peptide cleavage and single cell sorting, a chimeric antibody-antigen fusion protein that contained the variable domains of mouse IgG with a porcine IgA constant domain fused to the FedF antigen could be produced in CHO-K1 cells...
January 29, 2019: MAbs
Christof Regl, Therese Wohlschlager, Wolfgang Esser-Skala, Iris Wagner, Martin Samonig, Johann Holzmann, Christian G Huber
Monoclonal antibodies (mAbs) are widely applied as highly specific and efficient therapeutic agents for various medical conditions, including cancer, inflammatory and autoimmune diseases. As protein production in cellular systems inherently generates a multitude of molecular variants, manufacturing of mAbs requires stringent control in order to ensure safety and efficacy of the drugs. Moreover, monitoring of mAb variants in the course of the fermentation process may allow instant tuning of process parameters to maintain optimal cell culture conditions...
January 22, 2019: MAbs
Philippe Valadon, Sonia M Pérez-Tapia, Renae S Nelson, Omar U Guzmán-Bringas, Hugo I Arrieta-Oliva, Keyla M Gómez-Castellano, Mary Ann Pohl, Juan C Almagro
We describe here the design, construction and validation of ALTHEA Gold Libraries™. These single-chain variable fragment, semisynthetic libraries are built on synthetic human well-known IGHV and IGKV germline genes combined with natural human complementarity-determining region (CDR)-H3/JH (H3J) fragments. One IGHV gene provided a universal VH scaffold and was paired with two IGKV scaffolds to furnish different topographies for binding distinct epitopes. The scaffolds were diversified at positions identified as in contact with antigens in the known antigen-antibody complex structures...
January 20, 2019: MAbs
Patanachai Limpikirati, John E Hale, Mark Hazelbaker, Yongbo Huang, Zhiguang Jia, Mahdieh Yazdani, Eric M Graban, Robert C Vaughan, Richard W Vachet
Monoclonal antibodies are among the fastest growing therapeutics in the pharmaceutical industry. Detecting higher-order structure changes of antibodies upon storage or mishandling, however, is a challenging problem. In this study, we describe the use of diethylpyrocarbonate (DEPC)-based covalent labeling (CL) - mass spectrometry (MS) to detect conformational changes caused by heat stress, using rituximab as a model system. The structural resolution obtained from DEPC CL-MS is high enough to probe subtle conformation changes that are not detectable by common biophysical techniques...
January 13, 2019: MAbs
Gunasekaran Dhandapani, Assaf Howard, Thien Van Truong, Thekke V Baiju, Ellina Kesselman, Noga Friedman, Ellen Wachtel, Mordechai Sheves, Dganit Danino, Irishi N N Namboothiri, Guy Patchornik
We introduce a new concept and potentially general platform for antibody (Ab) purification that does not rely on chromatography or specific ligands (e.g., Protein A); rather, it makes use of detergent aggregates capable of efficiently capturing Ab while rejecting hydrophilic impurities. Captured Ab are then extracted from the aggregates in pure form without co-extraction of hydrophobic impurities or aggregate dissolution. The aggregates studied consist of conjugated "Engineered-micelles" built from the nonionic detergent, Tween-20; bathophenanthroline, a hydrophobic metal chelator, and Fe2+ ions...
January 8, 2019: MAbs
Madeline Neiveyans, Rana Melhem, Christophe Arnoult, Thomas Bourquard, Marta Jarlier, Muriel Busson, Adrien Laroche, Martine Cerutti, Martine Pugnières, David Ternant, Nadège Gaborit, Thierry Chardès, Anne Poupon, Valérie Gouilleux-Gruart, Andre Pèlegrin, Marie-Alix Poul
Targeting transferrin receptor 1 (TfR1) with monoclonal antibodies is a promising therapeutic strategy in cancer as tumor cells often overexpress TfR1 and show increased iron needs. We have re-engineered six anti-human TfR1 single-chain variable fragment (scFv) antibodies into fully human scFv2 -Fcγ1 and IgG1 antibodies. We selected the more promising candidate (H7), based on its ability to inhibit TfR1-mediated iron-loaded transferrin internalization in Raji cells (B-cell lymphoma). The H7 antibody displayed nanomolar affinity for its target in both formats (scFv2 -Fcγ1 and IgG1), but cross-reacted with mouse TfR1 only in the scFv2 -Fc format...
January 3, 2019: MAbs
Stanley Chung, Jun Tian, Zhijun Tan, Jie Chen, Na Zhang, Yunping Huang, Erik Vandermark, Jongchan Lee, Michael Borys, Zheng Jian Li
Controlling acidic charge variants is critical for an industrial bioprocess due to the potential impact on therapeutic efficacy and safety. Achieving a consistent charge variant profile at manufacturing scale remains challenging and may require substantial resources to investigate effective control strategies. This is partially due to incomplete understanding of the underlying causes for charge variant formation during the cell culture process. To address this gap, we examined the effects of four process input factors (temperature, iron concentration, feed media age, and antioxidant (rosmarinic acid) concentration) on charge variant profile...
January 3, 2019: MAbs
Robert G Brinson, John P Marino, Frank Delaglio, Luke W Arbogast, Ryan M Evans, Anthony Kearsley, Geneviève Gingras, Houman Ghasriani, Yves Aubin, Gregory K Pierens, Xinying Jia, Mehdi Mobli, Hamish G Grant, David W Keizer, Kristian Schweimer, Jonas Ståhle, Göran Widmalm, Edward R Zartler, Chad W Lawrence, Patrick N Reardon, John R Cort, Ping Xu, Feng Ni, Saeko Yanaka, Koichi Kato, Stuart R Parnham, Desiree Tsao, Andreas Blomgren, Torgny Rundlöf, Nils Trieloff, Peter Schmieder, Alfred Ross, Ken Skidmore, Kang Chen, David Keire, Darón I Freedberg, Thea Suter-Stahel, Gerhard Wider, Gregor Ilc, Janez Plavec, Scott A Bradley, Donna M Baldisseri, Mauricio Luis Sforça, Ana Carolina de Mattos Zeri, Julie Yu Wei, Christina M Szabo, Carlos A Amezcua, John B Jordan, Mats Wikström
The increased interest in using monoclonal antibodies (mAbs) as a platform for biopharmaceuticals has led to the need for new analytical techniques that can precisely assess physicochemical properties of these large and very complex drugs for the purpose of correctly identifying quality attributes (QA). One QA, higher order structure (HOS), is unique to biopharmaceuticals and essential for establishing consistency in biopharmaceutical manufacturing, detecting process-related variations from manufacturing changes and establishing comparability between biologic products...
December 20, 2018: MAbs
Yue Tong, Xu Fang, Hong Tian, Shengwei Zhong, Liang Jin, Xiangdong Gao, Wenbing Yao
In vitro immunization can to used to produce monoclonal antibodies(mAbs), but this technology is limited by poor reproducibility and the requirement of pre-immunized lymphocytes. To improve this approach, we recently developed a method for rapid generation of antigen-specific B cells. Here, we report the application of this system to the production of human IgGs against tumor necrosis factor (TNF). We expressed mutant proteins with site-specific incorporated p-nitrophenylalanine (pNO2 Phe), which stimulated an in vitro immune response in human immune cells...
December 20, 2018: MAbs
Eric Hatterer, Leticia Barba, Nelly Noraz, Bruno Daubeuf, Jean-Pierre Aubry-Lachainaye, Benoit von der Weid, Françoise Richard, Marie Kosco-Vilbois, Walter Ferlin, Limin Shang, Vanessa Buatois
CD19 is a B cell-specific receptor that regulates the threshold of B cell receptor (BCR)-mediated cell proliferation. A CD47xCD19 bispecific antibody (biAb) was generated to target and deplete B cells via multiple antibody-mediated mechanisms. Interestingly, the biAb, constructed of a CD19 binding arm and a CD47 binding arm, inhibited BCR-mediated B-cell proliferation with an effect even more potent than a CD19 monoclonal antibody (mAb). The inhibitory effect of the biAb was not attributable to CD47 binding because a monovalent or bivalent anti-CD47 mAb had no effect on B cell proliferation...
December 19, 2018: MAbs
Ayse Meric Ovacik, Ji Li, Marie Lemper, Dimitry Danilenko, Nicola Stagg, Mary Mathieu, Diego Ellerman, Vinita Gupta, Navdeep Kalia, Trung Nguy, Vicki Plaks, Clarissa David Johnson, Weiru Wang, Jochen Brumm, Bernard Fine, Teemu Junttila, Kedan Lin, Paul J Carter, Saileta Prabhu, Christoph Spiess, Amrita V Kamath
Bispecific antibody production using single host cells has been a new advancement in the antibody engineering field. We previously showed comparable in vitro biological activity and in vivo mouse pharmacokinetics (PK) for two novel single cell variants (v10 and v11) and one traditional dual cell in vitro-assembled anti-human epidermal growth factor receptor 2/CD3 T-cell dependent bispecific (TDB) antibodies. Here, we extended our previous work to assess single cell-produced bispecific variants of a novel TDB against FcRH5, a B-cell lineage marker expressed on multiple myeloma (MM) tumor cells...
December 14, 2018: MAbs
Yingda Xu, Dongdong Wang, Bruce Mason, Tony Rossomando, Ning Li, Dingjiang Liu, Jason K Cheung, Wei Xu, Smita Raghava, Amit Katiyar, Christine Nowak, Tao Xiang, Diane D Dong, Joanne Sun, Alain Beck, Hongcheng Liu
Increasing attention has been paid to developability assessment with the understanding that thorough evaluation of monoclonal antibody lead candidates at an early stage can avoid delays during late-stage development. The concept of developability is based on the knowledge gained from the successful development of approximately 80 marketed antibody and Fc-fusion protein drug products and from the lessons learned from many failed development programs over the last three decades. Here, we reviewed antibody quality attributes that are critical to development and traditional and state-of-the-art analytical methods to monitor those attributes...
December 13, 2018: MAbs
William J J Finlay, James E Coleman, Jonathan S Edwards, Kevin S Johnson
Monoclonal anti-programmed cell death 1 (PD1) antibodies are successful cancer therapeutics, but it is not well understood why individual antibodies should have idiosyncratic side-effects. As the humanized antibody SHR-1210 causes capillary hemangioma in patients, a unique toxicity amongst anti-PD1 antibodies, we performed human receptor proteome screening to identify nonspecific interactions that might drive angiogenesis. This screen identified that SHR-1210 mediated aberrant, but highly selective, low affinity binding to human receptors such as vascular endothelial growth factor receptor 2 (VEGFR2), frizzled class receptor 5 and UL16 binding protein 2 (ULBP2)...
December 12, 2018: MAbs
Catherine J Hutchings, Paul Colussi, Theodore G Clark
It is now well established that antibodies have numerous potential benefits when developed as therapeutics. Here, we evaluate the technical challenges of raising antibodies to membrane-spanning proteins together with enabling technologies that may facilitate the discovery of antibody therapeutics to ion channels. Additionally, we discuss the potential targeting opportunities in the anti-ion channel antibody landscape, along with a number of case studies where functional antibodies that target ion channels have been reported...
December 10, 2018: MAbs
Xiaojun Lu, R Paul Nobrega, Heather Lynaugh, Tushar Jain, Kyle Barlow, Todd Boland, Arvind Sivasubramanian, Maximiliano Vásquez, Yingda Xu
Contemporary in vivo and in vitro discovery platform technologies greatly increase the odds of identifying high-affinity monoclonal antibodies (mAbs) towards essentially any desired biologically relevant epitope. Lagging discovery throughput is the ability to select for highly developable mAbs with drug-like properties early in the process. Upstream consideration of developability metrics should reduce the frequency of failures in later development stages. As the field moves towards incorporating biophysical screening assays in parallel to discovery processes, similar approaches should also be used to ensure robust chemical stability...
December 10, 2018: MAbs
Andrew Kroetsch, Chunxia Qiao, Mairead Heavey, Leiming Guo, Dhaval K Shah, Sheldon Park
A new modality in antibody engineering has emerged in which the antigen affinity is designed to be pH dependent (PHD). In particular, combining high affinity binding at neutral pH with low affinity binding at acidic pH leads to a novel antibody that can more effectively neutralize the target antigen while avoiding antibody-mediated antigen accumulation. Here, we studied how the in vivo pharmacokinetics of the superantigen, Staphylococcal enterotoxin B (SEB), is affected by an engineered antibody with pH-dependent binding...
December 7, 2018: MAbs
Jhih-Wei Jian, Hong-Sen Chen, Yi-Kai Chiu, Hung-Pin Peng, Chao-Ping Tung, Ing-Chien Chen, Chung-Ming Yu, Yueh-Liang Tsou, Wei-Ying Kuo, Hung-Ju Hsu, An-Suei Yang
Antibodies provide immune protection by recognizing antigens of diverse chemical properties, but elucidating the amino acid sequence-function relationships underlying the specificity and affinity of antibody-antigen interactions remains challenging. We designed and constructed phage-displayed synthetic antibody libraries with enriched protein antigen-recognition propensities calculated with machine learning predictors, which indicated that the designed single-chain variable fragment variants were encoded with enhanced distributions of complementarity-determining region (CDR) hot spot residues with high protein antigen recognition propensities in comparison with those in the human antibody germline sequences...
December 7, 2018: MAbs
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