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  • Potent neutralizing monoclonal antibodies against Ebola virus isolated from vaccinated donors
    mAbs (IF 4.405) 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

    ABSTRACT 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

  • NHDL, a recombinant VL/VH hybrid antibody control for IgG2/4 antibodies.
    mAbs (IF 4.405) 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

  • Analytical characterization of coformulated antibodies as combination therapy
    mAbs (IF 4.405) Pub Date : 2020-03-21
    Jun Kim; Yoen Joo Kim; Mingyan Cao; Niluka De Mel; Methal Albarghouthi; Kenneth Miller; Jared S. Bee; Jihong Wang; Xiangyang Wang

    ABSTRACT 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

  • Targeting a membrane-proximal epitope on mesothelin increases the tumoricidal activity of a bispecific antibody blocking CD47 on mesothelin-positive tumors
    mAbs (IF 4.405) 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

    ABSTRACT 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

  • Interaction analysis of glycoengineered antibodies with CD16a: a native mass spectrometry approach
    mAbs (IF 4.405) Pub Date : 2020-03-13
    Joanna Hajduk; Cyrill Brunner; Sebastian Malik; Jana Bangerter; Gisbert Schneider; Marco Thomann; Dietmar Reusch; Renato Zenobi

    ABSTRACT 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

  • Intein mediated high throughput screening for bispecific antibodies
    mAbs (IF 4.405) Pub Date : 2020-03-09
    Tim Hofmann; Johannes Schmidt; Elke Ciesielski; Stefan Becker; Thomas Rysiok; Mark Schütte; Lars Toleikis; Harald Kolmar; Achim Doerner

    ABSTRACT 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

  • HX008: a humanized PD-1 blocking antibody with potent antitumor activity and superior pharmacologic properties.
    mAbs (IF 4.405) 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

  • Understanding the human antibody repertoire.
    mAbs (IF 4.405) 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

  • 10th European immunogenicity platform open symposium on immunogenicity of biopharmaceuticals.
    mAbs (IF 4.405) 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

  • Anti-ErbB2 immunotherapeutics: struggling to make better antibodies for cancer therapy.
    mAbs (IF 4.405) 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

  • 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 4.405) 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

  • Restricted epitope specificity determined by variable region germline segment pairing in rodent antibody repertoires.
    mAbs (IF 4.405) 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

  • Exploiting next-generation sequencing in antibody selections – a simple PCR method to recover binders
    mAbs (IF 4.405) 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

  • A novel human monoclonal antibody specific to the A33 glycoprotein recognizes colorectal cancer and inhibits metastasis.
    mAbs (IF 4.405) Pub Date : 2020-01-12
    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

  • Improved translation of stability for conjugated antibodies using an in vitro whole blood assay.
    mAbs (IF 4.405) 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

  • 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 4.405) 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

  • In situ antibody phage display yields optimal inhibitors of integrin α11/β1.
    mAbs (IF 4.405) 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

  • 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 4.405) 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

  • Functional activity of anti-LINGO-1 antibody opicinumab requires target engagement at a secondary binding site.
    mAbs (IF 4.405) Pub Date : 2020-01-12
    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

  • Discovery and characterization of single-domain antibodies for polymeric Ig receptor-mediated mucosal delivery of biologics.
    mAbs (IF 4.405) Pub Date : 2020-01-06
    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

  • Molecular mechanism of an antagonistic antibody against glucose-dependent insulinotropic polypeptide receptor.
    mAbs (IF 4.405) Pub Date : 2020-01-04
    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

  • T cell epitope mapping of secukinumab and ixekizumab in healthy donors.
    mAbs (IF 4.405) 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

  • VHH antibody targeting the chemokine receptor CX3CR1 inhibits progression of atherosclerosis.
    mAbs (IF 4.405) 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

  • The impact of proline isomerization on antigen binding and the analytical profile of a trispecific anti-HIV antibody.
    mAbs (IF 4.405) Pub Date : 2019
    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

  • Homogeneous antibody-drug conjugates: DAR 2 anti-HER2 obtained by conjugation on isolated light chain followed by mAb assembly.
    mAbs (IF 4.405) 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

  • Rapid two-dimensional Protein-A size exclusion chromatography of monoclonal antibodies for titer and aggregation measurements from harvested cell culture fluid samples.
    mAbs (IF 4.405) 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

  • Antibodies to watch in 2020.
    mAbs (IF 4.405) Pub Date : 2019-12-17
    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

  • Design and characterization of mouse IgG1 and IgG2a bispecific antibodies for use in syngeneic models.
    mAbs (IF 4.405) 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

  • Harnessing MerTK agonism for targeted therapeutics.
    mAbs (IF 4.405) 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

  • 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 4.405) 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

  • Clinical pharmacology of vc-MMAE antibody-drug conjugates in cancer patients: learning from eight first-in-human Phase 1 studies.
    mAbs (IF 4.405) 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

  • Monitoring glycation levels of a bispecific monoclonal antibody at subunit level by ultrahigh-resolution MALDI FT-ICR mass spectrometry.
    mAbs (IF 4.405) 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

  • Regulation of antibody-mediated complement-dependent cytotoxicity by modulating the intrinsic affinity and binding valency of IgG for target antigen.
    mAbs (IF 4.405) 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

  • An engineered human IgG1 CH2 domain with decreased aggregation and nonspecific binding.
    mAbs (IF 4.405) 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

  • Dissecting the molecular basis of high viscosity of monospecific and bispecific IgG antibodies.
    mAbs (IF 4.405) 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

  • Structure-based engineering of pH-dependent antibody binding for selective targeting of solid-tumor microenvironment.
    mAbs (IF 4.405) 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

  • Development of a high yielding expression platform for the introduction of non-natural amino acids in protein sequences.
    mAbs (IF 4.405) 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

  • Defining the right diluent for intravenous infusion of therapeutic antibodies.
    mAbs (IF 4.405) 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

  • 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 4.405) 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

  • Heparin chromatography as an in vitro predictor for antibody clearance rate through pinocytosis.
    mAbs (IF 4.405) 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

  • In vivo safety profile of a CSPG4-directed IgE antibody in an immunocompetent rat model.
    mAbs (IF 4.405) 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

  • Glycosylation-independent binding of monoclonal antibody toripalimab to FG loop of PD-1 for tumor immune checkpoint therapy.
    mAbs (IF 4.405) Pub Date : 2019-04-19
    Hongchuan Liu,Lijing Guo,Jing Zhang,Yuehua Zhou,Jinwei Zhou,Jian Yao,Hai Wu,Sheng Yao,Bo Chen,Yan Chai,Jianxun Qi,George F Gao,Shuguang Tan,Hui Feng,Jinghua Yan

    Monoclonal antibody (mAb)-based blockade of programmed cell death 1 (PD-1) or its ligand to enable antitumor T-cell immunity has been successful in treating multiple tumors. However, the structural basis of the binding mechanisms of the mAbs and PD-1 and the effects of glycosylation of PD-1 on mAb interaction are not well understood. Here, we report the complex structure of PD-1 with toripalimab, a

  • Monitoring therapeutic monoclonal antibodies in brain tumor.
    mAbs (IF 4.405) Pub Date : 2014-12-09
    Rima Ait-Belkacem,Caroline Berenguer,Claude Villard,L'Houcine Ouafik,Dominique Figarella-Branger,Alain Beck,Olivier Chinot,Daniel Lafitte

    Bevacizumab induces normalization of abnormal blood vessels, making them less leaky. By binding to vascular endothelial growth factor, it indirectly attacks the vascular tumor mass. The optimal delivery of targeted therapies including monoclonal antibodies or anti-angiogenesis drugs to the target tissue highly depends on the blood-brain barrier permeability. It is therefore critical to investigate

  • Characterization of a plant-produced recombinant human secretory IgA with broad neutralizing activity against HIV.
    mAbs (IF 4.405) Pub Date : 2014-12-09
    Matthew Paul,Rajko Reljic,Katja Klein,Pascal M W Drake,Craig van Dolleweerd,Martin Pabst,Markus Windwarder,Elsa Arcalis,Eva Stoger,Friedrich Altmann,Catherine Cosgrove,Angela Bartolf,Susan Baden,Julian K-C Ma

    Recombinant Secretory IgA (SIgA) complexes have the potential to improve antibody-based passive immunotherapeutic approaches to combat many mucosal pathogens. In this report, we describe the expression, purification and characterization of a human SIgA format of the broadly neutralizing anti-HIV monoclonal antibody (mAb) 2G12, using both transgenic tobacco plants and transient expression in Nicotiana

  • Antibody-drug conjugate model fast characterization by LC-MS following IdeS proteolytic digestion.
    mAbs (IF 4.405) Pub Date : 2014-07-10
    Elsa Wagner-Rousset,Marie-Claire Janin-Bussat,Olivier Colas,Melissa Excoffier,Daniel Ayoub,Jean-François Haeuw,Ian Rilatt,Michel Perez,Nathalie Corvaïa,Alain Beck

    Here we report the design and production of an antibody-fluorophore conjugate (AFC) as a non-toxic model of an antibody-drug conjugate (ADC). This AFC is based on the conjugation of dansyl sulfonamide ethyl amine (DSEA )-linker maleimide on interchain cysteines of trastuzumab used as a reference antibody. The resulting AFC was first characterized by routine analytical methods (SEC, SDS-PAGE, CE-SDS

  • High throughput detection of antibody self-interaction by bio-layer interferometry.
    mAbs (IF 4.405) Pub Date : 2013-09-03
    Tingwan Sun,Felicia Reid,Yuqi Liu,Yuan Cao,Patricia Estep,Claire Nauman,Yingda Xu

    Self-interaction of an antibody may lead to aggregation, low solubility or high viscosity. Rapid identification of highly developable leads remains challenging, even though progress has been made with the introduction of techniques such as self-interaction chromatography (SIC) and cross-interaction chromatography (CIC). Here, we report a high throughput method to detect antibody clone self-interaction

  • Lessons for the clinic from rituximab pharmacokinetics and pharmacodynamics.
    mAbs (IF 4.405) Pub Date : 2013-08-13
    Josée Golay,Gianpietro Semenzato,Alessandro Rambaldi,Robin Foà,Gianluca Gaidano,Enrica Gamba,Fabrizio Pane,Antonello Pinto,Giorgina Specchia,Francesco Zaja,Mario Regazzi

    The anti-CD20 antibody rituximab (RTX; Rituxan®, MabThera®) was the first anti-cancer antibody approved by the US Food and Drug Administration in 1997 and it is now the most-studied unconjugated therapeutic antibody. The knowledge gained over the past 15 y on the pharmacodynamics (PD) of this antibody has led to the development of a new generation of anti-CD20 antibodies with enhanced efficacy in vitro

  • Immunogenicity of mAbs in non-human primates during nonclinical safety assessment.
    mAbs (IF 4.405) Pub Date : 2013-08-09
    Peter J K van Meer,Marlous Kooijman,Vera Brinks,Christine C Gispen-de Wied,Beatriz Silva-Lima,Ellen H M Moors,Huub Schellekens

    The immunogenicity of biopharmaceuticals used in clinical practice remains an unsolved challenge in drug development. Non-human primates (NHPs) are often the only relevant animal model for the development of monoclonal antibodies (mAbs), but the immune response of NHPs to therapeutic mAbs is not considered to be predictive of the response in humans because of species differences. In this study, we

  • Highly efficient selection of epitope specific antibody through competitive yeast display library sorting.
    mAbs (IF 4.405) Pub Date : 2013-06-15
    Vinita Puri,Emily Streaker,Ponraj Prabakaran,Zhongyu Zhu,Dimiter S Dimitrov

    Combinatory antibody library display technologies have been invented and successfully implemented for the selection and engineering of therapeutic antibodies. Precise targeting of important epitopes on the protein of interest is essential for such isolated antibodies to serve as effective modulators of molecular interactions. We developed a strategy to efficiently isolate antibodies against a specific

  • The cost-effectiveness of biopharmaceuticals: a look at the evidence.
    mAbs (IF 4.405) Pub Date : 2012-03-02
    Andrew W Wilson,Peter J Neumann

    Due to the increasing availability and costs of biopharmaceuticals, policymakers are questioning whether they provide good value relative to other health interventions and many are increasingly relying on cost-utility analyses (CUAs) to supplement decision-making. Analyzing data from the Tufts Medical Center Cost-Effectiveness Analysis Registry, this study critically reviewed the cost-utility literature

  • The Antibody Society.
    mAbs (IF 4.405) Pub Date : 2010-04-29
    Andrew Bradbury

  • In vitro potency, pharmacokinetic profiles, and pharmacological activity of optimized anti-IL-21R antibodies in a mouse model of lupus.
    mAbs (IF 4.405) Pub Date : 2010-04-29
    Yulia Vugmeyster,Heath Guay,Pamela Szklut,Ming D Qian,Macy Jin,Angela Widom,Vikki Spaulding,Frann Bennett,Leslie Lowe,Tatyana Andreyeva,David Lowe,Steven Lane,George Thom,Viia Valge-Archer,Davinder Gill,Deborah Young,Laird Bloom

    Using phage display, we generated a panel of optimized neutralizing antibodies against the human and mouse receptors for interleukin 21 (IL-21), a cytokine that is implicated in the pathogenesis of many types of autoimmune disease. Two antibodies, Ab-01 and Ab-02, which differed by only four amino acids in V(L) CDR3, showed potent inhibition of human and mouse IL-21R in cell-based assays and were evaluated

  • Correction
    mAbs (IF 4.405) Pub Date : 2019-10-24

    (2019). Correction. mAbs: Vol. 11, No. 8, pp. 1-1.

  • Direct measurement of light and heavy antibody chains using ion mobility and middle-down mass spectrometry.
    mAbs (IF 4.405) Pub Date : 2019-10-13
    Rafael D Melani,Kristina Srzentić,Vincent R Gerbasi,John P McGee,Romain Huguet,Luca Fornelli,Neil L Kelleher

    The analysis of monoclonal antibodies (mAbs) by a middle-down mass spectrometry (MS) approach is a growing field that attracts the attention of many researchers and biopharmaceutical companies. Usually, liquid fractionation techniques are used to separate mAbs polypeptides chains before MS analysis. Gas-phase fractionation techniques such as high-field asymmetric waveform ion mobility spectrometry

  • Native peptide mapping - A simple method to routinely monitor higher order structure changes and relation to functional activity.
    mAbs (IF 4.405) Pub Date : 2019-10-04
    Michel Degueldre,Annemie Wielant,Eglantine Girot,Will Burkitt,John O'Hara,Gaël Debauve,Annick Gervais,Carl Jone

    In the biopharmaceutical environment, controlling the Critical Quality Attributes (CQA) of a product is essential to prevent changes that affect its safety or efficacy. Physico-chemical techniques and bioassays are used to screen and monitor these CQAs. The higher order structure (HOS) is a CQA that is typically studied using techniques that are not commonly considered amenable to quality control laboratories

  • Identification and characterization of an IgG sequence variant with an 11 kDa heavy chain C-terminal extension using a combination of mass spectrometry and high-throughput sequencing analysis.
    mAbs (IF 4.405) Pub Date : 2019-10-01
    Claire Harris,Weichen Xu,Luigi Grassi,Chunlei Wang,Abigail Markle,Colin Hardman,Richard Stevens,Guillermo Miro-Quesada,Diane Hatton,Jihong Wang

    Protein primary structure is a potential critical quality attribute for biotherapeutics. Identifying and characterizing any sequence variants present is essential for product development. A sequence variant ~11 kDa larger than the expected IgG mass was observed by size-exclusion chromatography and two-dimensional liquid chromatography coupled with online mass spectrometry. Further characterization

  • Insights into the IgG heavy chain engineering patent landscape as applied to IgG4 antibody development.
    mAbs (IF 4.405) Pub Date : 2019-09-26
    Christophe Dumet,Jérémy Pottier,Valérie Gouilleux-Gruart,Hervé Watier

    Despite being the least abundant immunoglobulin G in human plasma, IgG4 are used therapeutically when weak effector functions are needed. The increase in engineered IgG4-based antibodies on the market led us to study the patent landscape of IgG4 Fc engineering, i.e., patents claiming modifications in the heavy chain. Thirty-seven relevant patent families were identified, comprising hundreds of IgG4

  • DuoMab: a novel CrossMab-based IgG-derived antibody format for enhanced antibody-dependent cell-mediated cytotoxicity.
    mAbs (IF 4.405) Pub Date : 2019-09-17
    Claudio Sustmann,Steffen Dickopf,Jörg T Regula,Hubert Kettenberger,Michael Mølhøj,Christian Gassner,Diana Weininger,Sebastian Fenn,Tobias Manigold,Lothar Kling,Klaus-Peter Künkele,Manfred Schwaiger,Birgit Bossenmaier,Julia J Griese,Karl-Peter Hopfner,Alexandra Graff-Meyer,Henning Stahlberg,Philippe Ringler,Matthias E Lauer,Ulrich Brinkmann,Wolfgang Schaefer,Christian Klein

    High specificity accompanied with the ability to recruit immune cells has made recombinant therapeutic antibodies an integral part of drug development. Here we present a generic approach to generate two novel IgG-derived antibody formats that are based on a modification of the CrossMab technology. MoAbs harbor two heavy chains (HCs) resulting in one binding entity and one fragment crystallizable region

  • Optimization of a calcium-dependent Protein A-derived domain for mild antibody purification.
    mAbs (IF 4.405) Pub Date : 2019-09-17
    Julia Scheffel,Sara Kanje,Jesper Borin,Sophia Hober

    As reported here, we developed and optimized a purification matrix based on a Protein A-derived domain, ZCa, displaying calcium-dependent antibody binding. It provides an alternative to the acidic elution conditions of conventional Protein A affinity chromatography for purification of sensitive antibodies and other Fc-based molecules. We describe the multimerization of ZCa to generate a chromatography

  • Antibody discovery and engineering by enhanced CRISPR-Cas9 integration of variable gene cassette libraries in mammalian cells.
    mAbs (IF 4.405) Pub Date : 2019-09-16
    Cristina Parola,Daniel Neumeier,Simon Friedensohn,Lucia Csepregi,Mariangela Di Tacchio,Derek M Mason,Sai T Reddy

    Antibody engineering in mammalian cells offers the important advantage of expression and screening of libraries in their native conformation, increasing the likelihood of generating candidates with more favorable molecular properties. Major advances in cellular engineering enabled by CRISPR-Cas9 genome editing have made it possible to expand the use of mammalian cells in biotechnological applications

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全球疫情及响应:BMC Medicine专题征稿