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  • Characterization of concurrent target suppression by JNJ-61178104, a bispecific antibody against human tumor necrosis factor and interleukin-17A.
    mAbs (IF 4.634) Pub Date : 2020-06-16
    Songmao Zheng,Fang Shen,Brian Jones,Damien Fink,Brian Geist,Ivo Nnane,Zhao Zhou,Jeff Hall,Ravi Malaviya,Tatiana Ort,Weirong Wang

    ABSTRACT Tumor necrosis factor (TNF) and interleukin (IL)-17A are pleiotropic cytokines implicated in the pathogenesis of several autoimmune diseases including rheumatoid arthritis (RA) and psoriatic arthritis (PsA). JNJ-61178104 is a novel human anti-TNF and anti-IL-17A monovalent, bispecific antibody that binds to both human TNF and human IL-17A with high affinities and blocks the binding of TNF

    更新日期:2020-06-16
  • Potent neutralization of SARS-CoV-2 by human antibody heavy-chain variable domains isolated from a large library with a new stable scaffold.
    mAbs (IF 4.634) Pub Date : 2020-06-16
    Zehua Sun,Chuan Chen,Wei Li,David R Martinez,Aleksandra Drelich,Du-San Baek,Xianglei Liu,John W Mellors,Chien-Te Tseng,Ralph S Baric,Dimiter S Dimitrov

    ABSTRACT Effective therapies are urgently needed for COVID-19. Here we describe the identification of a new stable human immunoglobulin G1 heavy-chain variable (VH) domain scaffold that was used for the construction of a large library, lCAT6, of engineered human VHs. This library was panned against the receptor-binding domain (RBD) of the SARS-CoV-2 spike (S) glycoprotein. Two VH domains (VH ab6 and

    更新日期:2020-06-16
  • Ig-like ACE2 protein therapeutics: A revival in development during the COVID-19 pandemic.
    mAbs (IF 4.634) Pub Date : 2020-06-16
    Kewen Qian,Shi Hu

    ABSTRACT While the potential therapeutic utility of angiotensin-converting enzyme 2 (ACE2) is well established, the clinical development of ACE2 drugs has been limited, likely due in part to the short half-life of the protein. In contrast, Ig-like ACE2 fusion proteins have exhibited greatly extended plasma half-life in vivo, and they have been shown to have a potent neutralization effect against SARS-CoV-2

    更新日期:2020-06-16
  • Biomanufacturing evolution from conventional to intensified processes for productivity improvement: a case study.
    mAbs (IF 4.634) Pub Date : 2020-06-08
    Jianlin Xu,Xuankuo Xu,Chao Huang,James Angelo,Christopher L Oliveira,Mengmeng Xu,Xia Xu,Deniz Temel,Julia Ding,Sanchayita Ghose,Michael C Borys,Zheng Jian Li

    ABSTRACT Process intensification has shown great potential to increase productivity and reduce costs in biomanufacturing. This case study describes the evolution of a manufacturing process from a conventional processing scheme at 1000-L scale (Process A, n = 5) to intensified processing schemes at both 1000-L (Process B, n = 8) and 2000-L scales (Process C, n = 3) for the production of a monoclonal

    更新日期:2020-06-08
  • Influence of physiochemical properties on the subcutaneous absorption and bioavailability of monoclonal antibodies.
    mAbs (IF 4.634) Pub Date : 2020-06-03
    Amita Datta-Mannan,Selina Estwick,Chen Zhou,Hiuwan Choi,Nicole E Douglass,Derrick R Witcher,Jirong Lu,Catherine Beidler,Rohn Millican

    ABSTRACT Many therapeutic monoclonal antibodies (mAbs) were initially developed for intravenous (IV) administration. As a means to improve mAb drug-ability and the patient experience, subcutaneous (SC) administration is an increasingly important delivery route for mAbs. Unlike IV administration, bioavailability limitations for antibodies have been reported following SC injection and can dictate whether

    更新日期:2020-06-03
  • Enabling speed to clinic for monoclonal antibody programs using a pool of clones for IND-enabling toxicity studies.
    mAbs (IF 4.634) Pub Date : 2020-05-25
    Parimala Bolisetty,Gabi Tremml,Sen Xu,Anurag Khetan

    ABSTRACT The importance of speed to clinic for medicines that may address unmet medical needs puts pressure on product development timelines. Historically, both toxicology and first-in-human clinical materials are generated using the same clonal-derived cells to ensure safety and minimize any development risks. However, cell line development with single cell cloning is time consuming, and aggravated

    更新日期:2020-05-25
  • Benchmarking biopharmaceutical process development and manufacturing cost contributions to R&D.
    mAbs (IF 4.634) Pub Date : 2020-05-23
    Suzanne S Farid,Max Baron,Christos Stamatis,Wenhao Nie,Jon Coffman

    This study aims to benchmark and analyze the process development and manufacturing costs across the biopharmaceutical drug development cycle and their contribution to overall research and development (R&D) costs. This was achieved with a biopharmaceutical drug development lifecycle cost model that captured the costs, durations, risks and interdependencies of the clinical, process development and manufacturing

    更新日期:2020-05-23
  • Investigation of anomalous charge variant profile reveals discrete pH-dependent conformations and conformation-dependent charge states within the CDR3 loop of a therapeutic mAb.
    mAbs (IF 4.634) Pub Date : 2020-05-20
    Wenkui Lan,Joseph J Valente,Andrew Ilott,Naresh Chennamsetty,Zhihua Liu,Joseph M Rizzo,Aaron P Yamniuk,Difei Qiu,Holly M Shackman,Mark S Bolgar

    During the development of a therapeutic monoclonal antibody (mAb-1), the charge variant profile obtained by pH-gradient cation exchange chromatography (CEX) contained two main peaks, each of which exhibited a unique intrinsic fluorescence profile and demonstrated inter-convertibility upon reinjection of isolated peak fractions. Domain analysis of mAb-1 by CEX and liquid chromatography-mass spectrometry

    更新日期:2020-05-20
  • Hyphenation of strong cation exchange chromatography to native mass spectrometry for high throughput online characterization of charge heterogeneity of therapeutic monoclonal antibodies.
    mAbs (IF 4.634) Pub Date : 2020-05-20
    Fengfei Ma,Fahimeh Raoufi,Marc Andre Bailly,Laurence Fayadat-Dilman,Daniela Tomazela

    Characterization of charge heterogeneity in monoclonal antibodies (mAbs) is needed during developability assessment and downstream development of drug candidates. Charge heterogeneity can come from post-translational modifications like deamidation, isomerization, and sialylation. Elucidation of charge variants with mass spectrometry (MS) has historically been challenging. Due to the nonvolatility and

    更新日期:2020-05-20
  • Post-hoc assessment of the immunogenicity of three antibodies reveals distinct immune stimulatory mechanisms.
    mAbs (IF 4.634) Pub Date : 2020-05-18
    Robin E Walsh,Megan Lannan,Yi Wen,Xiaoli Wang,Christopher A Moreland,Jill Willency,Michael D Knierman,Laura Spindler,Ling Liu,Wei Zeng,Guilherme V Rocha,Victor Obungu,Jirong Lu,Arunan Kaliyaperumal,Andrea Ferrante,Robert Siegel,Laurent P Malherbe

    Biologics have the potential to induce an immune response when used therapeutically. A number of in vitro assays are currently used preclinically to predict the risk of immunogenicity, but the validation of these preclinical tools suffers from the relatively small number of accessible immunogenic molecules and the limited understanding of the mechanisms underlying the immunogenicity of biologics. Here

    更新日期:2020-05-18
  • Human-likeness of antibody biologics determined by back-translation and comparison with large antibody variable gene repertoires.
    mAbs (IF 4.634) Pub Date : 2020-05-13
    Samuel Schmitz,Cinque Soto,James E Crowe,Jens Meiler

    The antibody (Ab) germline gene rearrangement of variable (V), diversity (D), and joining (J) gene segments, as well as somatic hypermutation, give rise to the human Ab variable gene sequence repertoire. It is common to characterize single nucleotide frequencies of the variable region by alignment to species-specific wildtype germline genes. The increasing application of next-generation sequencing

    更新日期:2020-05-13
  • Rapid identification of highly potent human anti-GPCR antagonist monoclonal antibodies.
    mAbs (IF 4.634) Pub Date : 2020-04-29
    Martin J Scott,Amanda Jowett,Martin Orecchia,Peter Ertl,Larissa Ouro-Gnao,Julia Ticehurst,David Gower,John Yates,Katie Poulton,Carol Harris,Michael J Mullin,Kathrine J Smith,Alan P Lewis,Nick Barton,Michael L Washburn,Ruud de Wildt

    Complex cellular targets such as G protein-coupled receptors (GPCRs), ion channels, and other multi-transmembrane proteins represent a significant challenge for therapeutic antibody discovery, primarily because of poor stability of the target protein upon extraction from cell membranes. To assess whether a limited set of membrane-bound antigen formats could be exploited to identify functional antibodies

    更新日期:2020-04-29
  • Rapid identification of highly potent human anti-GPCR antagonist monoclonal antibodies
    mAbs (IF 4.634) Pub Date : 2020-04-28
    Martin J. Scott; Amanda Jowett; Martin Orecchia; Peter Ertl; Larissa Ouro-Gnao; Julia Ticehurst; David Gower; John Yates; Katie Poulton; Carol Harris; Michael J. Mullin; Kathrine J. Smith; Alan P. Lewis; Nick Barton; Michael L. Washburn; Ruud de Wildt

    ABSTRACT Complex cellular targets such as G protein-coupled receptors (GPCRs), ion channels, and other multi-transmembrane proteins represent a significant challenge for therapeutic antibody discovery, primarily because of poor stability of the target protein upon extraction from cell membranes. To assess whether a limited set of membrane-bound antigen formats could be exploited to identify functional

    更新日期:2020-04-28
  • In vitro affinity optimization of an anti-BDNF monoclonal antibody translates to improved potency in targeting chronic pain states in vivo.
    mAbs (IF 4.634) Pub Date : 2020-04-24
    Edwina Stack,Sheridan McMurray,Gordon McMurray,Jason Wade,Melissa Clark,Gareth Young,Kim Marquette,Sadhana Jain,Kerry Kelleher,Ting Chen,Qingcong Lin,Laird Bloom,Laura Lin,William Finlay,Rie Suzuki,Orla Cunningham

    The role of brain-derived neurotrophic factor (BDNF) signaling in chronic pain has been well documented. Given the important central role of BDNF in long term plasticity and memory, we sought to engineer a high affinity, peripherally-restricted monoclonal antibody against BDNF to modulate pain. BDNF shares 100% sequence homology across human and rodents; thus, we selected chickens as an alternative

    更新日期:2020-04-24
  • Multimeric antibodies with increased valency surpassing functional affinity and potency thresholds using novel formats.
    mAbs (IF 4.634) Pub Date : 2020-04-22
    Ami Miller,Stephen Carr,Terry Rabbitts,Hanif Ali

    The success of therapeutic antibodies is largely attributed for their exquisite specificity, homogeneity, and functionality. There is, however, a need to engineer antibodies to extend and enhance their potency. One parameter is functional affinity augmentation, since antibodies matured in vivo have a natural affinity threshold. Generation of multivalent antibodies is one option capable of surpassing

    更新日期:2020-04-23
  • In vivo safety profile of a CSPG4-directed IgE antibody in an immunocompetent rat model.
    mAbs (IF 4.634) Pub Date : 2019-11-26
    Iwan P Williams,Silvia Crescioli,Heng Sheng Sow,Heather J Bax,Carl Hobbs,Kristina M Ilieva,Elise French,Giulia Pellizzari,Vivienne Cox,Debra H Josephs,James F Spicer,Sophia N Karagiannis,Silvia Mele

    IgE monoclonal antibodies hold great potential for cancer therapy. Preclinical in vivo systems, particularly those in which the antibody recognizes the host species target antigen and binds to cognate Fc receptors, are often the closest approximation to human exposure and represent a key challenge for evaluating the safety of antibody-based therapies. We sought to develop an immunocompetent rat system

    更新日期:2020-04-20
  • Heparin chromatography as an in vitro predictor for antibody clearance rate through pinocytosis.
    mAbs (IF 4.634) Pub Date : 2019-11-26
    Thomas E Kraft,Wolfgang F Richter,Thomas Emrich,Alexander Knaupp,Michaela Schuster,Andreas Wolfert,Hubert Kettenberger

    The pharmacokinetic (PK) properties of therapeutic antibodies directly affect efficacy, dose and dose intervals, application route and tissue penetration. In indications where health-care providers and patients can choose between several efficacious and safe therapeutic options, convenience (determined by dosing interval or route of application), which is mainly driven by PK properties, can affect

    更新日期:2020-04-20
  • Native size-exclusion chromatography-mass spectrometry: suitability for antibody-drug conjugate drug-to-antibody ratio quantitation across a range of chemotypes and drug-loading levels.
    mAbs (IF 4.634) Pub Date : 2019-11-26
    Jay Jones,Laura Pack,Joshua H Hunter,John F Valliere-Douglass

    Native size-exclusion chromatography-mass spectrometry (nSEC-MS) is an analytical methodology that is appropriate for accurately quantitating the drug-to-antibody ratio (DAR) on a wide variety of interchain cysteine-linked antibody-drug conjugates (ADCs), irrespective of chemotype. In the current preclinical environment, novel ADCs conjugated with unique drug-linkers need to progress toward the clinic

    更新日期:2020-04-20
  • NHDL, a recombinant VL/VH hybrid antibody control for IgG2/4 antibodies.
    mAbs (IF 4.634) Pub Date : 2019-11-27
    Corinna Lau,Martin Berner McAdam,Grethe Bergseth,Algirdas Grevys,Jack Ansgar Bruun,Judith Krey Ludviksen,Hilde Fure,Terje Espevik,Anders Moen,Jan Terje Andersen,Tom Eirik Mollnes

    The mechanism of action of recombinant IgG2/4 antibodies involves blocking of their target without the induction of effector functions. Examples are eculizumab (Soliris®), which is used clinically to block complement factor C5, as well as anti-human CD14 (r18D11) and anti-porcine CD14 (rMIL2) produced in our laboratory. So far, no proper IgG2/4 control antibody has been available for controlled validation

    更新日期:2020-04-20
  • Defining the right diluent for intravenous infusion of therapeutic antibodies.
    mAbs (IF 4.634) Pub Date : 2019-11-27
    Shen Luo,Keisha Melodi McSweeney,Tao Wang,Silvia M Bacot,Gerald M Feldman,Baolin Zhang

    Therapeutic monoclonal antibodies (mAbs) are commonly administered to patients through intravenous (IV) infusion, which involves diluting the medication into an infusion solution (e.g., saline and 5% dextrose). Using the wrong diluent can cause product aggregation, which may compromise patient safety. We and others have shown that Herceptin® (trastuzumab) and Avastin® (bevacizumab) undergo rapid aggregation

    更新日期:2020-04-20
  • Development of a high yielding expression platform for the introduction of non-natural amino acids in protein sequences.
    mAbs (IF 4.634) Pub Date : 2019-11-27
    Gargi Roy,Jason Reier,Andrew Garcia,Tom Martin,Megan Rice,Jihong Wang,Meagan Prophet,Ronald Christie,William Dall'Acqua,Sanjeev Ahuja,Michael A Bowen,Marcello Marelli

    The ability to genetically encode non-natural amino acids (nnAAs) into proteins offers an expanded tool set for protein engineering. nnAAs containing unique functional moieties have enabled the study of post-translational modifications, protein interactions, and protein folding. In addition, nnAAs have been developed that enable a variety of biorthogonal conjugation chemistries that allow precise and

    更新日期:2020-04-20
  • Dissecting the molecular basis of high viscosity of monospecific and bispecific IgG antibodies.
    mAbs (IF 4.634) Pub Date : 2019-11-28
    Cholpon Tilegenova,Saeed Izadi,Jianping Yin,Christine S Huang,Jiansheng Wu,Diego Ellerman,Sarah G Hymowitz,Benjamin Walters,Cleo Salisbury,Paul J Carter

    Some antibodies exhibit elevated viscosity at high concentrations, making them poorly suited for therapeutic applications requiring administration by injection such as subcutaneous or ocular delivery. Here we studied an anti-IL-13/IL-17 bispecific IgG4 antibody, which has anomalously high viscosity compared to its parent monospecific antibodies. The viscosity of the bispecific IgG4 in solution was

    更新日期:2020-04-20
  • Structure-based engineering of pH-dependent antibody binding for selective targeting of solid-tumor microenvironment.
    mAbs (IF 4.634) Pub Date : 2019-11-28
    Traian Sulea,Nazanin Rohani,Jason Baardsnes,Christopher R Corbeil,Christophe Deprez,Yuneivy Cepero-Donates,Alma Robert,Joseph D Schrag,Marie Parat,Mélanie Duchesne,Maria L Jaramillo,Enrico O Purisima,John C Zwaagstra

    Recent development of monoclonal antibodies as mainstream anticancer agents demands further optimization of their safety for use in humans. Potent targeting and/or effector activities on normal tissues is an obvious toxicity concern. Optimization of specific tumor targeting could be achieved by taking advantage of the extracellular acidity of solid tumors relative to normal tissues. Here, we applied

    更新日期:2020-04-20
  • An engineered human IgG1 CH2 domain with decreased aggregation and nonspecific binding.
    mAbs (IF 4.634) Pub Date : 2019-12-03
    Guangcan Cao,Xinyu Gao,Yancheng Zhan,Qingguang Wang,Zhe Zhang,Dimiter S Dimitrov,Rui Gong

    The immunoglobulin (Ig) CH2 domain is a promising scaffold for the development of candidate therapeutics. We have previously shown that the stability of isolated CH2 could be increased by the introduction of an additional disulfide bond and removal of seven N-terminal residues (m01s). However, both isolated CH2 and m01s aggregate, likely due to the existence of aggregation-prone regions (APRs) that

    更新日期:2020-04-20
  • Regulation of antibody-mediated complement-dependent cytotoxicity by modulating the intrinsic affinity and binding valency of IgG for target antigen.
    mAbs (IF 4.634) Pub Date : 2019-12-12
    Bo Wang,Chunning Yang,Xiaofang Jin,Qun Du,Herren Wu,William Dall'Acqua,Yariv Mazor

    Complement-dependent cytotoxicity (CDC) is a potent effector mechanism, engaging both innate and adaptive immunity. Although strategies to improve the CDC activity of antibody therapeutics have primarily focused on enhancing the interaction between the antibody crystallizable fragment (Fc) and the first subcomponent of the C1 complement complex (C1q), the relative importance of intrinsic affinity and

    更新日期:2020-04-20
  • Clinical pharmacology of vc-MMAE antibody-drug conjugates in cancer patients: learning from eight first-in-human Phase 1 studies.
    mAbs (IF 4.634) Pub Date : 2019-12-18
    Chunze Li,Cindy Zhang,Zao Li,Divya Samineni,Dan Lu,Bei Wang,Shang-Chiung Chen,Rong Zhang,Priya Agarwal,Bernard M Fine,Sandhya Girish

    vc-MMAE antibody-drug conjugates (ADCs) consist of a monoclonal antibody (mAb) covalently bound with a potent anti-mitotic toxin (MMAE) through a protease-labile valine-citrulline (vc) linker. The objective of this study was to characterize the pharmacokinetics (PK) and explore exposure-response relationships of eight vc-MMAE ADCs, against different targets and for diverse tumor indications, using

    更新日期:2020-04-20
  • Development of a quantitative relationship between CAR-affinity, antigen abundance, tumor cell depletion and CAR-T cell expansion using a multiscale systems PK-PD model.
    mAbs (IF 4.634) Pub Date : 2019-12-18
    Aman P Singh,Xirong Zheng,Xiefan Lin-Schmidt,Wenbo Chen,Thomas J Carpenter,Alice Zong,Weirong Wang,Donald L Heald

    The development of mechanism-based, multiscale pharmacokinetic-pharmacodynamic (PK-PD) models for chimeric antigen receptor (CAR)-T cells is needed to enable investigation of in vitro and in vivo correlation of CAR-T cell responses and to facilitate preclinical-to-clinical translation. Toward this goal, we first developed a cell-level in vitro PD model that quantitatively characterized CAR-T cell-induced

    更新日期:2020-04-20
  • Harnessing MerTK agonism for targeted therapeutics.
    mAbs (IF 4.634) Pub Date : 2019-12-18
    Vivekananda Kedage,Diego Ellerman,Yongmei Chen,Wei-Ching Liang,Joven Borneo,Yan Wu,Minhong Yan

    Phagocytosis plays important roles both in homeostasis and under pathological conditions. Fcγ receptor-mediated phagocytosis has been exploited as an integral mechanism for antibody-based therapies. Unlike Fcγ receptor-mediated phagocytosis, MerTK-mediated phagocytic clearance is immunologically silent. Here, we describe a bispecific antibody approach to harness MerTK for targeted clearance without

    更新日期:2020-04-20
  • Monitoring glycation levels of a bispecific monoclonal antibody at subunit level by ultrahigh-resolution MALDI FT-ICR mass spectrometry.
    mAbs (IF 4.634) Pub Date : 2019-12-18
    Christoph Gstöttner,Dietmar Reusch,Markus Haberger,Irina Dragan,Peter Van Veelen,David P A Kilgour,Yury O Tsybin,Yuri E M van der Burgt,Manfred Wuhrer,Simone Nicolardi

    Bispecific monoclonal antibodies (BsAbs) are engineered proteins with multiple functionalities and properties. The "bi-specificity" of these complex biopharmaceuticals is a key characteristic for the development of novel and more effective therapeutic strategies. The high structural complexity of BsAbs poses a challenge to the analytical methods needed for their characterization. Modifications of the

    更新日期:2020-04-20
  • Design and characterization of mouse IgG1 and IgG2a bispecific antibodies for use in syngeneic models.
    mAbs (IF 4.634) Pub Date : 2019-12-19
    Feng Wang,Jordan C Tsai,Jonathan H Davis,Bryant Chau,Jia Dong,Sean M West,Jason M Hogan,Matthew L Wheeler,Christine Bee,Winse Morishige,Thomas Cayton,Donata David-Brown,Chengyue Zhang,Alexander Kozhich,Tim Sproul,Gavin Dollinger,Arvind Rajpal,Pavel Strop

    The development of antibody therapeutics relies on animal models that accurately recapitulate disease biology. Syngeneic mouse models are increasingly used with new molecules to capture the biology of complex cancers and disease states, and to provide insight into the role of the immune system. The establishment of syngeneic mouse models requires the ability to generate surrogate mouse counterparts

    更新日期:2020-04-20
  • Antibodies to watch in 2020.
    mAbs (IF 4.634) Pub Date : 2019-12-26
    Hélène Kaplon,Mrinalini Muralidharan,Zita Schneider,Janice M Reichert

    This 2020 installment of the annual 'Antibodies to Watch' series documents the antibody therapeutics approved in 2019 and in regulatory review in the United States or European Union, as well as those in late-stage clinical studies, as of November 2019*. At this time, a total of 5 novel antibody therapeutics (romosozumab, risankizumab, polatuzumab vedotin, brolucizumab, and crizanlizumab) had been granted

    更新日期:2020-04-20
  • Rapid two-dimensional Protein-A size exclusion chromatography of monoclonal antibodies for titer and aggregation measurements from harvested cell culture fluid samples.
    mAbs (IF 4.634) Pub Date : 2019-12-26
    Zachary D Dunn,Jayesh Desai,Gabriel M Leme,Dwight R Stoll,Douglas D Richardson

    The success of monoclonal antibody (mAb) therapeutics have increased pharmaceutical investment in mAb production, which has led to a greater demand of technologies to efficiently characterize these biotherapeutics. The large size and heterogeneity of mAbs require the measurement of multiple critical quality attributes (CQAs) during production. The current workflow to measure CQAs of antibodies involves

    更新日期:2020-04-20
  • Homogeneous antibody-drug conjugates: DAR 2 anti-HER2 obtained by conjugation on isolated light chain followed by mAb assembly.
    mAbs (IF 4.634) Pub Date : 2019-12-26
    Mercè Farràs,Joan Miret,Marc Camps,Ramón Román,Óscar Martínez,Xavier Pujol,Stéphane Erb,Anthony Ehkirch,Sarah Cianferani,Antoni Casablancas,Jordi Joan Cairó

    Despite advances in medical care, cancer remains a major threat to human health. Antibody-drug conjugates (ADCs) are a promising targeted therapy to overcome adverse side effects to normal tissues. In this field, the current challenge is obtaining homogeneous preparations of conjugates, where a defined number of drugs are conjugated to specific antibody sites. Site-directed cysteine-based conjugation

    更新日期:2020-04-20
  • VHH antibody targeting the chemokine receptor CX3CR1 inhibits progression of atherosclerosis.
    mAbs (IF 4.634) Pub Date : 2020-01-10
    Sarah Low,Haixia Wu,Kavita Jerath,Annette Tibolla,Birgit Fogal,Rebecca Conrad,Margit MacDougall,Steven Kerr,Valentina Berger,Rajvee Dave,Jorge Villalona,Lynn Pantages,Jennifer Ahlberg,Hua Li,Diane Van Hoorick,Cedric Ververken,John Broadwater,Alisa Waterman,Sanjaya Singh,Rachel Kroe-Barrett

    CX3CR1 has been identified as a highly attractive target for several therapeutic interventions. Despite this potential, no potent antagonists, either small molecule or monoclonal antibody, have been identified. Here we describe the lead finding and engineering approach that lead to the identification of BI 655088, a potent biotherapeutic antagonist to CX3CR1. BI 655088 is a potent CX3CR1 antagonist

    更新日期:2020-04-20
  • T cell epitope mapping of secukinumab and ixekizumab in healthy donors.
    mAbs (IF 4.634) Pub Date : 2020-01-10
    Sebastian Spindeldreher,Anette Karle,Evelyne Correia,Maxime Tenon,Sascha Gottlieb,Thomas Huber,Bernard Maillere,Frank Kolbinger

    Secukinumab, a human monoclonal antibody that selectively neutralizes IL-17A, has consistently shown low anti-drug antibody responses in patients with psoriasis, psoriatic arthritis, and ankylosing spondylitis. Secukinumab has also shown lower in vitro immunogenicity potential compared with other monoclonal antibodies used to treat psoriasis and psoriatic arthritis, and a significantly lower in vitro

    更新日期:2020-04-20
  • The impact of proline isomerization on antigen binding and the analytical profile of a trispecific anti-HIV antibody.
    mAbs (IF 4.634) Pub Date : 2020-01-10
    Alessandro Masiero,Lechat Nelly,Gentric Marianne,Sourrouille Christophe,Laville Florian,Crépin Ronan,Borel Claire,Ziegler Cornelia,Bisch Grégoire,Leclerc Eric,Laurent Ludovic,Brault Dominique,Alexandre Sylvie,Gagnaire Marie,Duffieux Francis,Soubrier Fabienne,Capdevila Cécile,Arnould Isabelle,Dumas Jacques,Dabin Jérôme,Genet Bruno,Radošević Katarina,Menet Jean-Michel,Prades Catherine

    Proline cis-trans conformational isomerization is a mechanism that affects different types of protein functions and behaviors. Using analytical characterization, structural analysis, and molecular dynamics simulations, we studied the causes of an aberrant two-peak size-exclusion chromatography profile observed for a trispecific anti-HIV antibody. We found that proline isomerization in the tyrosine-proline-proline

    更新日期:2020-04-20
  • Molecular mechanism of an antagonistic antibody against glucose-dependent insulinotropic polypeptide receptor.
    mAbs (IF 4.634) Pub Date : 2020-01-12
    Xiaoshan Min,Junming Yie,Jinghong Wang,Ben C Chung,Ching-Shin Huang,Haoda Xu,Jie Yang,Liying Deng,Joanne Lin,Qing Chen,Christina M Abbott,Caroline Gundel,Stephen A Thibault,Tina Meng,Darren L Bates,David J Lloyd,Murielle M Véniant,Zhulun Wang

    Glucose-dependent insulinotropic polypeptide (GIP) is an incretin hormone involved in regulating glucose and lipid metabolism. GIP receptor (GIPR) antagonism is believed to offer therapeutic potential for various metabolic diseases. Pharmacological intervention of GIPR, however, has limited success due to lack of effective antagonistic reagents. Previously we reported the discovery of two mouse anti-murine

    更新日期:2020-04-20
  • Discovery and characterization of single-domain antibodies for polymeric Ig receptor-mediated mucosal delivery of biologics.
    mAbs (IF 4.634) Pub Date : 2020-01-13
    Bharathikumar Vellalore Maruthachalam,Adam Zwolak,Xiefan Lin-Schmidt,Edward Keough,Ninkka Tamot,Sathya Venkataramani,Brian Geist,Sanjaya Singh,Rajkumar Ganesan

    Mucosal immunity is dominated by secretory IgA and IgM, although these are less favorable compared to IgG molecules for therapeutic development. Polymeric IgA and IgM are actively transported across the epithelial barrier via engagement of the polymeric Ig receptor (pIgR), but IgG molecules lack a lumen-targeted active transport mechanism, resulting in poor biodistribution of IgG therapeutics in mucosal

    更新日期:2020-04-20
  • Functional activity of anti-LINGO-1 antibody opicinumab requires target engagement at a secondary binding site.
    mAbs (IF 4.634) Pub Date : 2020-01-17
    Karl J M Hanf,Joseph W Arndt,YuTing Liu,Bang Jian Gong,Mia Rushe,Richelle Sopko,Ramiro Massol,Benjamin Smith,Yan Gao,Isin Dalkilic-Liddle,Xinhua Lee,Shanell Mojta,Zhaohui Shao,Sha Mi,R Blake Pepinsky

    LINGO-1 is a membrane protein of the central nervous system (CNS) that suppresses myelination of axons. Preclinical studies have revealed that blockade of LINGO-1 function leads to CNS repair in demyelinating animal models. The anti-LINGO-1 antibody Li81 (opicinumab), which blocks LINGO-1 function and shows robust remyelinating activity in animal models, is currently being investigated in a Phase 2

    更新日期:2020-04-20
  • SPLICELECT™: an adaptable cell surface display technology based on alternative splicing allowing the qualitative and quantitative prediction of secreted product at a single-cell level.
    mAbs (IF 4.634) Pub Date : 2020-01-19
    Christel Aebischer-Gumy,Pierre Moretti,Romain Ollier,Christelle Ries Fecourt,François Rousseau,Martin Bertschinger

    We describe a mammalian expression construct (SPLICELECT™) that allows the redirection of a proportion of a secreted protein onto the cell surface using alternative splicing: whereas the majority of the RNA is spliced into a transcript encoding a secreted protein, a weak splice donor site yields a secondary transcript encoding, in addition, a C-terminal transmembrane domain. The different sequence

    更新日期:2020-04-20
  • In situ antibody phage display yields optimal inhibitors of integrin α11/β1.
    mAbs (IF 4.634) Pub Date : 2020-01-24
    Eugenio Gallo,Abdellali Kelil,Peter E Bayliss,Ajitha Jeganathan,Olga Egorova,Lynda Ploder,Jarret A Adams,Patricia Giblin,Sachdev S Sidhu

    Integrins are transmembrane multi-conformation receptors that mediate interactions with the extracellular matrix. In cancer, integrins influence metastasis, proliferation, and survival. Collagen-binding integrin-α11/β1, a marker of aggressive tumors that is involved in stroma-tumor crosstalk, may be an attractive target for anti-cancer therapeutic antibodies. We performed selections with phage-displayed

    更新日期:2020-04-20
  • Investigation of the effect of salt additives in Protein L affinity chromatography for the purification of tandem single-chain variable fragment bispecific antibodies.
    mAbs (IF 4.634) Pub Date : 2020-01-25
    Serene W Chen,Darryl Tan,Yuan Sheng Yang,Wei Zhang

    Tandem single-chain variable fragment (scFv) bispecific antibodies (bsAb) are one of the most promising bsAb formats reported thus far. Yet, because of their increased aggregation propensity, high impurity content due to low expression level, smaller size and lack of the Fc region, it is challenging to isolate these products with high yield and purity within a limited number of purification steps in

    更新日期:2020-04-20
  • Improved translation of stability for conjugated antibodies using an in vitro whole blood assay.
    mAbs (IF 4.634) Pub Date : 2020-01-30
    Aimee Fourie-O'Donohue,Phillip Y Chu,Josefa Dela Cruz Chuh,Robert Tchelepi,Siao Ping Tsai,John C Tran,William S Sawyer,Dian Su,Carl Ng,Keyang Xu,Shang-Fan Yu,Thomas H Pillow,Jack Sadowsky,Peter S Dragovich,Yichin Liu,Katherine R Kozak

    For antibody-drug conjugates to be efficacious and safe, they must be stable in circulation to carry the payload to the site of the targeted cell. Several components of a drug-conjugated antibody are known to influence stability: 1) the site of drug attachment on the antibody, 2) the linker used to attach the payload to the antibody, and 3) the payload itself. In order to support the design and optimization

    更新日期:2020-04-20
  • A novel human monoclonal antibody specific to the A33 glycoprotein recognizes colorectal cancer and inhibits metastasis.
    mAbs (IF 4.634) Pub Date : 2020-02-03
    Patrizia Murer,Louis Plüss,Dario Neri

    Colorectal cancer represents the second most common cause of cancer-related death. The human A33 transmembrane glycoprotein is a validated tumor-associated antigen, expressed in 95% of primary and metastatic colorectal cancers. Using phage display technology, we generated a human monoclonal antibody (termed A2) specific to human A33 and we compared its epitope and performance to those of previously

    更新日期:2020-04-20
  • Exploiting next-generation sequencing in antibody selections – a simple PCR method to recover binders
    mAbs (IF 4.634) Pub Date : 2020-02-05
    Fortunato Ferrara; Andre A. Teixeira; Leslie Naranjo; M. Frank Erasmus; Sara D’Angelo; Andrew R.M. Bradbury

    ABSTRACT Antibody discovery using invitro display technologies such as phage and/or yeast display has become acornerstone in many research and development projects, including the creation of new drugs for clinical use. Traditionally, after the selection phase, random clones are isolated for binding validation and Sanger sequencing. More recently, next-generation sequencing (NGS) technology has allowed

    更新日期:2020-04-20
  • Restricted epitope specificity determined by variable region germline segment pairing in rodent antibody repertoires.
    mAbs (IF 4.634) Pub Date : 2020-02-10
    Yi-Chun Hsiao,Ying-Jiun J Chen,Leonard D Goldstein,Jia Wu,Zhonghua Lin,Kellen Schneider,Subhra Chaudhuri,Aju Antony,Kanika Bajaj Pahuja,Zora Modrusan,Dhaya Seshasayee,Somasekar Seshagiri,Isidro Hötzel

    Antibodies from B-cell clonal lineages share sequence and structural properties as well as epitope specificity. Clonally unrelated antibodies can similarly share sequence and specificity properties and are said to be convergent. Convergent antibody responses against several antigens have been described in humans and mice and include different classes of shared sequence features. In particular, some

    更新日期:2020-04-20
  • A functional antibody cross-reactive to both human and murine cytotoxic T-lymphocyte-associated protein 4 via binding to an N-glycosylation epitope.
    mAbs (IF 4.634) Pub Date : 2020-02-13
    Dong Li,Jing Li,Huanyu Chu,Zhuozhi Wang

    Cytotoxic T-lymphocyte-associated protein 4 (CTLA-4, CD152) is a receptor on T cells that inhibits the cell's functions. Blocking CTLA-4 with an antibody has proven effective for the treatment of cancer patients. Anti-CTLA-4 antibodies currently approved for clinical use can bind to human CTLA-4, but do not cross-react to murine CTLA-4. Here, we report the generation and characterization of a functional

    更新日期:2020-04-20
  • Anti-ErbB2 immunotherapeutics: struggling to make better antibodies for cancer therapy.
    mAbs (IF 4.634) Pub Date : 2020-02-13
    Rita De Santis

    Over the past 3 decades, monoclonal antibodies and their related derivatives, including recently approved antibody-drug conjugates, conquered a central role in cancer therapy because of their contribution to improve survival, time to progression and quality of life of patients compared to chemotherapy protocols. This review summarizes information on approved original and biosimilar products, as well

    更新日期:2020-04-20
  • 10th European immunogenicity platform open symposium on immunogenicity of biopharmaceuticals.
    mAbs (IF 4.634) Pub Date : 2020-02-16
    S Tourdot,A Abdolzade-Bavil,J Bessa,P Broët,A Fogdell-Hahn,M Giorgi,V Jawa,K Kuranda,N Legrand,S Pattijn,J A Pedras-Vasconcelos,A Rudy,P Salmikangas,D W Scott,V Snoeck,N Smith,S Spindeldreher,D Kramer

    Therapeutic proteins and emerging gene and cell-based therapies are attractive therapeutic tools for addressing unmet medical needs or when earlier conventional treatment approaches failed. However, the development of an immune response directed against therapeutic agents is a significant concern as it occurs in a substantial number of cases across products and indications. The specific anti-drug antibodies

    更新日期:2020-04-20
  • Understanding the human antibody repertoire.
    mAbs (IF 4.634) Pub Date : 2020-02-25
    Anthony R Rees

    The origins of the various elements in the human antibody repertoire have been and still are subject to considerable uncertainty. Uncertainty in respect of whether the various elements have always served a specific defense function or whether they were co-opted from other organismal roles to form a crude naïve repertoire that then became more complex as combinatorial mechanisms were added. Estimates

    更新日期:2020-04-20
  • HX008: a humanized PD-1 blocking antibody with potent antitumor activity and superior pharmacologic properties.
    mAbs (IF 4.634) Pub Date : 2020-02-27
    Jibin Zhang,Ying Huang,Gan Xi,Faming Zhang

    Through reactivating tumor-infiltrating lymphocytes, therapeutics targeting programmed cell death protein 1 (PD-1) demonstrate impressive clinical efficacy in the treatment of multiple cancers. In this report, we characterize HX008, a humanized IgG4S228P anti-PD-1 monoclonal antibody with an engineered Fc domain, in a series of in vitro assays and in vivo studies. In vitro, HX008 binds to human PD-1

    更新日期:2020-04-20
  • Intein mediated high throughput screening for bispecific antibodies.
    mAbs (IF 4.634) Pub Date : 2020-03-09
    Tim Hofmann,Johannes Schmidt,Elke Ciesielski,Stefan Becker,Thomas Rysiok,Mark Schütte,Lars Toleikis,Harald Kolmar,Achim Doerner

    Bispecific antibodies comprise extremely diverse architectures enabling complex modes of action, such as effector cell recruitment or conditional target modulation via dual targeting, not conveyed by monospecific antibodies. In recent years, research on bispecific therapeutics has substantially grown. However, evaluation of binding moiety combinations often leads to undesired prolonged development

    更新日期:2020-04-20
  • Interaction analysis of glycoengineered antibodies with CD16a: a native mass spectrometry approach.
    mAbs (IF 4.634) Pub Date : 2020-03-13
    Joanna Hajduk,Cyrill Brunner,Sebastian Malik,Jana Bangerter,Gisbert Schneider,Marco Thomann,Dietmar Reusch,Renato Zenobi

    Minor changes in the quality of biologically manufactured monoclonal antibodies (mAbs) can affect their bioactivity and efficacy. One of the most important variations concerns the N-glycosylation pattern, which directly affects an anti-tumor mechanism called antibody-dependent cell-meditated cytotoxicity (ADCC). Thus, careful engineering of mAbs is expected to enhance both protein-receptor binding

    更新日期:2020-04-20
  • Targeting a membrane-proximal epitope on mesothelin increases the tumoricidal activity of a bispecific antibody blocking CD47 on mesothelin-positive tumors.
    mAbs (IF 4.634) Pub Date : 2020-03-19
    Eric Hatterer,Xavier Chauchet,Françoise Richard,Leticia Barba,Valéry Moine,Laurence Chatel,Lucile Broyer,Guillemette Pontini,Tereza Bautzova,Flora Juan,Sebastien Calloud,Nicolas Bosson,Maud Charreton,Krzysztof Masternak,Vanessa Buatois,Limin Shang

    Mesothelin (MSLN) is a cell surface glycoprotein overexpressed in several solid malignancies, including gastric, lung, mesothelioma, pancreatic and ovarian cancers. While several MSLN-targeting therapeutic approaches are in development, only limited efficacy has been achieved in patients. A potential shortcoming of several described antibody-based approaches is that they target the membrane distal

    更新日期:2020-04-20
  • Analytical characterization of coformulated antibodies as combination therapy.
    mAbs (IF 4.634) Pub Date : 2020-03-06
    Jun Kim,Yoen Joo Kim,Mingyan Cao,Niluka De Mel,Methal Albarghouthi,Kenneth Miller,Jared S Bee,Jihong Wang,Xiangyang Wang

    When two therapeutic agents are combined in a single formulation, i.e., coformulated, the quality and safety of the individual agents must be preserved. Here we describe an approach to evaluate the quality attributes of two individual monoclonal antibodies (mAbs), designated mAb-A and mAb-B, in coformulation. The mAbs were fractionated from heat-stressed coformulated drug product (DP) by hydrophobic

    更新日期:2020-04-20
  • Potent neutralizing monoclonal antibodies against Ebola virus isolated from vaccinated donors.
    mAbs (IF 4.634) Pub Date : 2020-03-26
    Pengfei Fan,Xiangyang Chi,Guodong Liu,Guanying Zhang,Zhengshan Chen,Yujiao Liu,Ting Fang,Jianmin Li,Logan Banadyga,Shihua He,Changming Yu,Xiangguo Qiu,Wei Chen

    Ebola virus (EBOV) can cause severe hemorrhagic fever in humans, and no approved treatment is currently available. Although several antibodies have achieved good protection in animal models, the potential emerging isolates of ebolavirus and the unknown effects of experimental antibodies in humans underscore the need to develop additional antibodies to address the threat of Ebola. Here, we isolated

    更新日期:2020-04-20
  • Predicting Antibody Developability Profiles Through Early Stage Discovery Screening.
    mAbs (IF 4.634) Pub Date : 2020-04-05
    Marc Bailly,Carl Mieczkowski,Veronica Juan,Essam Metwally,Daniela Tomazela,Jeanne Baker,Makiko Uchida,Ester Kofman,Fahimeh Raoufi,Soha Motlagh,Yao Yu,Jihea Park,Smita Raghava,John Welsh,Michael Rauscher,Gopalan Raghunathan,Mark Hsieh,Yi-Ling Chen,Hang Thu Nguyen,Nhung Nguyen,Dan Cipriano,Laurence Fayadat-Dilman

    Monoclonal antibodies play an increasingly important role for the development of new drugs across multiple therapy areas. The term 'developability' encompasses the feasibility of molecules to successfully progress from discovery to development via evaluation of their physicochemical properties. These properties include the tendency for self-interaction and aggregation, thermal stability, colloidal

    更新日期:2020-04-20
  • Antibody CDR loops as ensembles in solution vs. canonical clusters from X-ray structures.
    mAbs (IF 4.634) Pub Date : 2020-04-07
    Monica L Fernández-Quintero,Martin C Heiss,Nancy D Pomarici,Barbara A Math,Klaus R Liedl

    In the past decade, the relevance of antibodies as therapeutics has increased substantially. Therefore, structural and functional characterization, in particular of the complementarity-determining regions (CDRs), is crucial to the design and engineering of antibodies with unique binding properties. Various studies have focused on classifying the CDR loops into a small set of main-chain conformations

    更新日期:2020-04-20
  • Dose escalation PET imaging for safety and effective therapy dose optimization of a bispecific antibody.
    mAbs (IF 4.634) Pub Date : 2020-04-10
    Yan Wang,Donghui Pan,Chenrong Huang,Bingliang Chen,Mingzhu Li,Shuaixiang Zhou,Lizhen Wang,Min Wu,Xinyu Wang,Yicong Bian,Junjie Yan,Junjian Liu,Min Yang,Liyan Miao

    Selecting the dose for efficacy and first-in-human studies of bispecific antibodies (BsAbs) is a challenging process. Herein, positron emission tomography (PET) imaging with 89Zr-labeled IBI322, an anti-CD47/PD-L1 BsAb, was used to optimize the safety and effective therapy dose. By labeling with 89Zr, we aimed to assess the pharmacokinetics (PK), safety, and target engagement of IBI322 with dose escalation

    更新日期:2020-04-20
  • Characterization of therapeutic proteins by cation exchange chromatography-mass spectrometry and top-down analysis.
    mAbs (IF 4.634) Pub Date : 2020-04-15
    Rachel Liuqing Shi,Gang Xiao,Thomas M Dillon,Margaret S Ricci,Pavel V Bondarenko

    Recently, cation exchange chromatography (CEX) using aqueous volatile buffers was directly coupled with mass spectrometry (MS) and applied for intact analysis of therapeutic proteins and antibodies. In our study, chemical modifications responsible for charge variants were identified by CEX-UV-MS for a monoclonal antibody (mAb), a bispecific antibody, and an Fc-fusion protein. We also report post-CEX

    更新日期:2020-04-20
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