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  • An accelerated surface-mediated stress assay of antibody instability for developability studies
    mAbs (IF 4.634) Pub Date : 2020-09-20
    Marie R.G. Kopp; Adriana-Michelle Wolf Pérez; Marta Virginia Zucca; Umberto Capasso Palmiero; Brigitte Friedrichsen; Nikolai Lorenzen; Paolo Arosio

    High physical stability is required for the development of monoclonal antibodies (mAbs) into successful therapeutic products. Developability assays are used to predict physical stability issues such as high viscosity and poor conformational stability, but protein aggregation remains a challenging property to predict. Among different types of stresses, air–water and solid–liquid interfaces are well

    更新日期:2020-09-20
  • Molecular computations of preferential interactions of proline, arginine.HCl, and NaCl with IgG1 antibodies and their impact on aggregation and viscosity
    mAbs (IF 4.634) Pub Date : 2020-09-17
    Theresa K. Cloutier; Chaitanya Sudrik; Neil Mody; Sathish A. Hasige; Bernhardt L. Trout

    Preferential interactions of excipients with the antibody surface govern their effect on the stability of antibodies in solution. We probed the preferential interactions of proline, arginine.HCl (Arg.HCl), and NaCl with three therapeutically relevant IgG1 antibodies via experiment and simulation. With simulations, we examined how excipients interacted with different types of surface patches in the

    更新日期:2020-09-18
  • Targeted IgMs agonize ocular targets with extended vitreal exposure
    mAbs (IF 4.634) Pub Date : 2020-09-16
    Yvonne Chen; Maciej Paluch; Julie A. Zorn; Sharmila Rajan; Brandon Leonard; Alberto Estevez; John Brady; Henry Chiu; Wilson Phung; Amin Famili; Minhong Yan; Claudio Ciferri; Marissa L. Matsumoto; Greg A. Lazar; Susan Crowell; Phil Hass; Nicholas J. Agard

    Treatment of ocular disease is hindered by the presence of the blood-retinal barrier, which restricts access of systemic drugs to the eye. Intravitreal injections bypass this barrier, delivering high concentrations of drug to the targeted tissue. However, the recommended dosing interval for approved biologics is typically 6–12 weeks, and frequent travel to the physician’s office poses a substantial

    更新日期:2020-09-16
  • Engineered Fc-glycosylation switch to eliminate antibody effector function.
    mAbs (IF 4.634) Pub Date : 2020-09-06
    Qun Zhou,Julie Jaworski,Yanfeng Zhou,Delphine Valente,Joanne Cotton,Denise Honey,Ekaterina Boudanova,Jochen Beninga,Ercole Rao,Ronnie Wei,Christine Mauriac,Clark Pan,Anna Park,Huawei Qiu

    Antibodies mediate effector functions through Fcγ receptor (FcγR) interactions and complement activation, causing cytokine release, degranulation, phagocytosis, and cell death. They are often undesired for development of therapeutic antibodies where only antigen binding or neutralization would be ideal. Effector elimination has been successful with extensive mutagenesis, but these approaches can potentially

    更新日期:2020-09-08
  • Measuring aggregates, self-association, and weak interactions in concentrated therapeutic antibody solutions
    mAbs (IF 4.634) Pub Date : 2020-09-04
    Sumit K. Chaturvedi; Arun Parupudi; Kristian Juul-Madsen; Ai Nguyen; Thomas Vorup-Jensen; Sonia Dragulin-Otto; Huaying Zhao; Reza Esfandiary; Peter Schuck

    Monoclonal antibodies are a class of biotherapeutics used for an increasing variety of disorders, including cancer, autoimmune, neurodegenerative, and viral diseases. Besides their antigen specificity, therapeutic use also mandates control of their solution interactions and colloidal properties in order to achieve a stable, efficacious, non-immunogenic, and low viscosity antibody solution at concentrations

    更新日期:2020-09-07
  • Biophysical and biochemical characterization of a VHH-based IgG-like bi- and trispecific antibody platform.
    mAbs (IF 4.634) Pub Date : 2020-09-04
    Lukas Pekar,Michael Busch,Bernhard Valldorf,Steffen C Hinz,Lars Toleikis,Simon Krah,Stefan Zielonka

    Here, we report the characterization of a VHH-derived IgG-like bi- and trispecific antibody platform that essentially relies on the replacement of the VH and VL regions of a conventional antibody by two independently functioning VHH domains. Consequently, a VHH is engrafted onto constant region CH1 while the other VHH-based paratope is engrafted on the constant region of the light chain, Cκ or Cλ,

    更新日期:2020-09-07
  • Biased anti-idiotype response in rabbits leads to high-affinity monoclonal antibodies to biologics
    mAbs (IF 4.634) Pub Date : 2020-09-04
    Christina Großerichter-Wagener; Dorien Kos; Astrid van Leeuwen; Lisanne Dijk; Jorn Jeremiasse; Floris C. Loeff; Theo Rispens

    Antibody formation to human(ized) therapeutic antibodies in humans is highly skewed toward anti-idiotype responses, probably because the idiotype is the only ‘foreign’ part of the antibody molecule. Here, we analyzed antibody responses to F(ab’)2 fragments of a panel of 17 human(ized) therapeutic antibodies in rabbits. Homology between the rabbit germline and the human(ized) antibodies is moderate

    更新日期:2020-09-07
  • Measuring aggregates, self-association, and weak interactions in concentrated therapeutic antibody solutions.
    mAbs (IF 4.634) Pub Date : 2020-09-06
    Sumit K Chaturvedi,Arun Parupudi,Kristian Juul-Madsen,Ai Nguyen,Thomas Vorup-Jensen,Sonia Dragulin-Otto,Huaying Zhao,Reza Esfandiary,Peter Schuck

    Monoclonal antibodies are a class of biotherapeutics used for an increasing variety of disorders, including cancer, autoimmune, neurodegenerative, and viral diseases. Besides their antigen specificity, therapeutic use also mandates control of their solution interactions and colloidal properties in order to achieve a stable, efficacious, non-immunogenic, and low viscosity antibody solution at concentrations

    更新日期:2020-09-06
  • Biased anti-idiotype response in rabbits leads to high-affinity monoclonal antibodies to biologics.
    mAbs (IF 4.634) Pub Date : 2020-09-06
    Christina Großerichter-Wagener,Dorien Kos,Astrid van Leeuwen,Lisanne Dijk,Jorn Jeremiasse,Floris C Loeff,Theo Rispens

    Antibody formation to human(ized) therapeutic antibodies in humans is highly skewed toward anti-idiotype responses, probably because the idiotype is the only 'foreign' part of the antibody molecule. Here, we analyzed antibody responses to F(ab')2 fragments of a panel of 17 human(ized) therapeutic antibodies in rabbits. Homology between the rabbit germline and the human(ized) antibodies is moderate

    更新日期:2020-09-06
  • Structural and functional characterization of C0021158, a high-affinity monoclonal antibody that inhibits Arginase 2 function via a novel non-competitive mechanism of action.
    mAbs (IF 4.634) Pub Date : 2020-09-03
    Mark Austin,Daniel Burschowsky,Denice T Y Chan,Lesley Jenkinson,Stuart Haynes,Agata Diamandakis,Chitra Seewooruthun,Alexandra Addyman,Sebastian Fiedler,Stephanie Ryman,Jessica Whitehouse,Louise H Slater,Andreas V Hadjinicolaou,Uzi Gileadi,Ellen Gowans,Yoko Shibata,Michelle Barnard,Teresa Kaserer,Pooja Sharma,Nadia M Luheshi,Robert W Wilkinson,Tristan J Vaughan,Sarah V Holt,Vincenzo Cerundolo,Mark D

    Arginase 2 (ARG2) is a binuclear manganese metalloenzyme that catalyzes the hydrolysis of L-arginine. The dysregulated expression of ARG2 within specific tumor microenvironments generates an immunosuppressive niche that effectively renders the tumor ‘invisible’ to the host’s immune system. Increased ARG2 expression leads to a concomitant depletion of local L-arginine levels, which in turn leads to

    更新日期:2020-09-03
  • CD40- and CD95-specific antibody single chain-Baff fusion proteins display BaffR-, TACI- and BCMA-restricted agonism.
    mAbs (IF 4.634) Pub Date : 2020-08-25
    Johannes Nelke,Juliane Medler,Daniela Weisenberger,Andreas Beilhack,Harald Wajant

    Antibodies that target a clinically relevant group of receptors within the tumor necrosis factor receptor superfamily (TNFRSF), including CD40 and CD95 (Fas/Apo-1), also require binding to Fc gamma receptors (FcγRs) to elicit a strong agonistic activity. This FcγR dependency largely relies on the mere cellular anchoring through the antibody’s Fc domain and does not involve the engagement of FcγR signaling

    更新日期:2020-08-25
  • Novel monoclonal antibodies to the SERINC5 HIV-1 restriction factor detect endogenous andvirion-associated SERINC5.
    mAbs (IF 4.634) Pub Date : 2020-08-23
    Sebastian Molnar,Lindsay Wieczorek,Michelle Zemil,Bianca Schulte,Elizabeth Martinez,Syna Gift,Lan Tang,Hendrik Streeck,Robert A Gramzinski,Nelson L Michael,Gordon Joyce,Victoria R Polonis

    ABSTRACT SERINC5 is a multi-pass transmembrane protein that is thought to play a role in serine incorporation during cellular membrane biosynthesis. This protein has also been identified as a human immunodeficiency virus Type 1 (HIV-1) restriction factor. The paucity of monoclonal antibodies (mAbs) against SERINC5 has posed a challenge for the study of the endogenous protein. Here we report the development

    更新日期:2020-08-23
  • AlbuCORE: an albumin-based molecular scaffold for multivalent biologics design.
    mAbs (IF 4.634) Pub Date : 2020-08-20
    Mario Sanches,Igor D'Angelo,Maria Jaramillo,Jason Baardsnes,John Zwaagstra,Joe Schrag,Ian Schoenhofen,Mauro Acchione,Sam Lawn,Grant Wickman,Nina Weisser,David K Y Poon,Gordon Ng,Surjit Dixit

    ABSTRACT As biologics have become a mainstay in the development of novel therapies, protein engineering tools to expand on their structural advantages, namely specificity, affinity, and valency are of interest. Antibodies have dominated this field as the preferred scaffold for biologics development while there has been limited exploration into the use of albumin with its unique physiological characteristics

    更新日期:2020-08-20
  • Assessment of the role of afucosylated glycoforms on the in vitro antibody-dependent phagocytosis activity of an antibody to Aβ aggregates.
    mAbs (IF 4.634) Pub Date : 2020-08-20
    Allyson Kwiatkowski,Carl Co,Sei Kameoka,An Zhang,John Coughlin,Tom Cameron,Eric Chiao,Svetlana Bergelson,Cullen Schmid Mason

    The terminal sugars of Fc glycans can influence the Fc-dependent biological activities of monoclonal antibody therapeutics. Afucosylated N-glycans have been shown to significantly alter binding to FcγRIIIa and affect antibody-dependent cell-mediated cytotoxicity (ADCC). Therefore, in order to maintain and ensure safety and efficacy for antibodies whose predominant mechanism of action (MOA) is ADCC

    更新日期:2020-08-20
  • Assessment of the role of afucosylated glycoforms on the in vitro antibody-dependent phagocytosis activity of an antibody to Aβ aggregates
    mAbs (IF 4.634) Pub Date : 2020-08-19
    Allyson Kwiatkowski; Carl Co; Sei Kameoka; An Zhang; John Coughlin; Tom Cameron; Eric Chiao; Svetlana Bergelson; Cullen Schmid Mason

    ABSTRACT The terminal sugars of Fc glycans can influence the Fc-dependent biological activities of monoclonal antibody therapeutics. Afucosylated N-glycans have been shown to significantly alter binding to FcγRIIIa and affect antibody-dependent cell-mediated cytotoxicity (ADCC). Therefore, in order to maintain and ensure safety and efficacy for antibodies whose predominant mechanism of action (MOA)

    更新日期:2020-08-19
  • A novel biparatopic hybrid antibody-ACE2 fusion that blocks SARS-CoV-2 infection: implications for therapy.
    mAbs (IF 4.634) Pub Date : 2020-08-18
    Xiaoniu Miao,Yi Luo,Xi Huang,Suki M Y Lee,Zhijun Yuan,Yongzhou Tang,Liandi Chen,Chao Wang,Fan Wu,Yifeng Xu,Wenchao Jiang,Wei Gao,Xuedong Song,Yao Yan,Tuling Pang,Cheng Chen,Yuefeng Zou,Weihui Fu,Liping Wan,Javier Gilbert-Jaramillo,Michael Knight,Tiong Kit Tan,Pramila Rijal,Alain Townsend,Joanne Sun,Xiaolin Liu,William James,Andy Tsun,Yingda Xu

    In the absence of a proven effective vaccine preventing infection by SARS-CoV-2, or a proven drug to treat COVID-19, the positive results of passive immune therapy using convalescent serum provide a strong lead. We have developed a new class of tetravalent, biparatopic therapy, 89C8-ACE2. It combines the specificity of a monoclonal antibody (89C8) that recognizes the relatively conserved N-terminal

    更新日期:2020-08-18
  • A novel biparatopic hybrid antibody-ACE2 fusion that blocks SARS-CoV-2 infection: implications for therapy
    mAbs (IF 4.634) Pub Date : 2020-08-17
    Xiaoniu Miao; Yi Luo; Xi Huang; Suki M. Y. Lee; Zhijun Yuan; Yongzhou Tang; Liandi Chen; Chao Wang; Fan Wu; Yifeng Xu; Wenchao Jiang; Wei Gao; Xuedong Song; Yao Yan; Tuling Pang; Cheng Chen; Yuefeng Zou; Weihui Fu; Liping Wan; Javier Gilbert-Jaramillo; Michael Knight; Tiong Kit Tan; Pramila Rijal; Alain Townsend; Joanne Sun; Xiaolin Liu; William James; Andy Tsun; Yingda Xu

    ABSTRACT In the absence of a proven effective vaccine preventing infection by SARS-CoV-2, or a proven drug to treat COVID-19, the positive results of passive immune therapy using convalescent serum provide a strong lead. We have developed a new class of tetravalent, biparatopic therapy, 89C8-ACE2. It combines the specificity of a monoclonal antibody (89C8) that recognizes the relatively conserved N-terminal

    更新日期:2020-08-17
  • Antigen physiochemical properties allosterically effect the IgG Fc-region and Fc neonatal receptor affinity.
    mAbs (IF 4.634) Pub Date : 2020-08-14
    Yue Sun,Alberto Estevez,Tilman Schlothauer,Aaron T Wecksler

    ABSTRACT The neonatal Fc receptor (FcRn) is a key membrane protein that plays an integral role in serum immunoglobulin (IgG) recycling, which extends the half-life of antibody. In addition, FcRn is known to traffic antigen-bound immunoglobulins (Ag-IgGs), and to interact with immune complexes to facilitate the antigen cross-presentation of peptides derived from the immune complexes in antigen-presenting

    更新日期:2020-08-14
  • Affinity maturation of antibodies by combinatorial codon mutagenesis versus error-prone PCR.
    mAbs (IF 4.634) Pub Date : 2020-08-11
    Jan Fredrik Simons,Yoong Wearn Lim,Kyle P Carter,Ellen K Wagner,Nicholas Wayham,Adam S Adler,David S Johnson

    ABSTRACT In vitro affinity maturation of therapeutic monoclonal antibodies is commonly applied to achieve desired properties, such as improved binding kinetics and affinity. Currently there are no universally accepted protocols for generation of variegated antibody libraries or selection thereof. Here, we performed affinity maturation using a yeast-based single-chain variable fragment (scFv) expression

    更新日期:2020-08-11
  • Malignant tissues produce divergent antibody glycosylation of relevance for cancer gene therapy effectiveness.
    mAbs (IF 4.634) Pub Date : 2020-08-04
    Dominik Brücher,Vojtech Franc,Sheena N Smith,Albert J R Heck,Andreas Plückthun

    ABSTRACT Gene therapy approaches now allow for the production of therapeutic antibodies by healthy or cancerous human tissues directly in vivo, and, with an increasing number of gene delivery methods available, the cell type for expression can be chosen. Yet, little is known about the biophysical changes introduced by expressing antibodies from producer cells or tissues targeted by gene therapy approaches

    更新日期:2020-08-04
  • The Antibody Society's antibody validation webinar series.
    mAbs (IF 4.634) Pub Date : 2020-08-04
    Jan L A Voskuil,Anita Bandrowski,C Glenn Begley,Andrew R M Bradbury,Andrew D Chalmers,Aldrin V Gomes,Travis Hardcastle,Fridtjof Lund-Johansen,Andreas Plückthun,Giovanna Roncador,Alejandra Solache,Michael J Taussig,James S Trimmer,Cecilia Williams,Simon L Goodman

    ABSTRACT In the wake of the reproducibility crisis and numerous discussions on how commercially available antibodies as research tool contribute to it, The Antibody Society developed a series of 10 webinars to address the issues involved. The webinars were delivered by speakers with both academic and commercial backgrounds. This report highlights the problems, and offers solutions to help the scientific

    更新日期:2020-08-04
  • A general evidence-based sequence variant control limit for recombinant therapeutic protein development.
    mAbs (IF 4.634) Pub Date : 2020-08-02
    Aming Zhang,Zhengwei Chen,Meinuo Li,Haibo Qiu,Shawn Lawrence,Hanne Bak,Ning Li

    ABSTRACT Sequence variants (SVs) resulting from unintended amino acid substitutions in recombinant therapeutic proteins have increasingly gained attention from both regulatory agencies and the biopharmaceutical industry given their potential impact on efficacy and safety. With well-optimized production systems, such sequence variants usually exist at very low levels in the final protein products due

    更新日期:2020-08-02
  • Bivalent binding on cells varies between anti-CD20 antibodies and is dose-dependent.
    mAbs (IF 4.634) Pub Date : 2020-08-02
    Sina Bondza,Toine Ten Broeke,Marika Nestor,Jeanette H W Leusen,Jos Buijs

    ABSTRACT Based on their mechanism of action, two types of anti-CD20 antibodies are distinguished: Type I, which efficiently mediate complement-dependent cytotoxicity, and Type II, which instead are more efficient in inducing direct cell death. Several molecular characteristics of these antibodies have been suggested to underlie these different biological functions, one of these being the manner of

    更新日期:2020-08-02
  • Conjugation of a peptide to an antibody engineered with free cysteines dramatically improves half-life and activity.
    mAbs (IF 4.634) Pub Date : 2020-08-02
    Raul C Camacho,Seohee You,Katharine E D'Aquino,Wenyu Li,Yuanping Wang,Joseph Gunnet,James Littrell,Jian Shen Qi,Lijuan Kang,Wenying Jian,Mary MacDonald,Timothy Tat,Derek Steiner,Yue-Mei Zhang,James Lanter,Raymond Patch,Rui Zhang,Jiali Li,Suzanne Edavettal,Wilson Edwards,Thai Dinh,Li Ying Wang,Judy Connor,Michael Hunter,Ellen Chi,Ronald V Swanson,James N Leonard,Martin A Case

    ABSTRACT The long circulating half-life and inherently bivalent architecture of IgGs provide an ideal vehicle for presenting otherwise short-lived G-protein-coupled receptor agonists in a format that enables avidity-driven enhancement of potency. Here, we describe the site-specific conjugation of a dual agonist peptide (an oxyntomodulin variant engineered for potency and in vivo stability) to the

    更新日期:2020-08-02
  • Development and validation of an LC-MS/MS method for simultaneous quantification of co-administered trastuzumab and pertuzumab.
    mAbs (IF 4.634) Pub Date : 2020-08-02
    Sandor Schokker,Fabrizia Fusetti,Francesco Bonardi,Remco J Molenaar,Ron A A Mathôt,Hanneke W M van Laarhoven

    ABSTRACT Given the increasing use of combination therapy with multiple monoclonal antibodies (mAbs), there is a clinical need for multiplexing assays. For the frequently co-administered anti-human epidermal growth factor receptor 2 (HER2) mAbs trastuzumab and pertuzumab, we developed a high-throughput and robust hybrid ligand-binding liquid chromatography-mass spectrometry (LC–MS)/MS quantitative assay

    更新日期:2020-08-02
  • Novel chimerized IgA CD20 antibodies: Improving neutrophil activation against CD20-positive malignancies.
    mAbs (IF 4.634) Pub Date : 2020-08-02
    Mitchell Evers,Toine Ten Broeke,J H Marco Jansen,Maaike Nederend,Firas Hamdan,Karli R Reiding,Saskia Meyer,Petra Moerer,Iris Brinkman,Thies Rösner,Robert Jan Lebbink,Thomas Valerius,Jeanette H W Leusen

    ABSTRACT Current combination therapies elicit high response rates in B cell malignancies, often using CD20 antibodies as the backbone of therapy. However, many patients eventually relapse or develop progressive disease. Therefore, novel CD20 antibodies combining multiple effector mechanisms were generated. To study whether neutrophil-mediated destruction of B cell malignancies can be added to the arsenal

    更新日期:2020-08-02
  • COBRA™: a highly potent conditionally active T cell engager engineered for the treatment of solid tumors.
    mAbs (IF 4.634) Pub Date : 2020-07-19
    Anand Panchal,Pui Seto,Russell Wall,Brian J Hillier,Ying Zhu,Jessica Krakow,Aakash Datt,Elizabeth Pongo,Andisheh Bagheri,Tseng-Hui T Chen,Jeremiah D Degenhardt,Patricia A Culp,Danielle E Dettling,Maia V Vinogradova,Chad May,Robert B DuBridge

    ABSTRACT Conditionally active COBRA™ (COnditional Bispecific Redirected Activation) T cell engagers are engineered to overcome the limitations of inherently active first-generation T cell engagers, which are unable to discern between tumor and healthy tissues. Designed to be administered as prodrugs, COBRAs target cell surface antigens upon administration, but engage T cells only after they are activated

    更新日期:2020-07-20
  • Rational optimization of a monoclonal antibody improves the aggregation propensity and enhances the CMC properties along the entire pharmaceutical process chain.
    mAbs (IF 4.634) Pub Date : 2020-07-13
    Joschka Bauer,Sven Mathias,Sebastian Kube,Kerstin Otte,Patrick Garidel,Martin Gamer,Michaela Blech,Simon Fischer,Anne R Karow-Zwick

    ABSTRACT The discovery of therapeutic monoclonal antibodies (mAbs) primarily focuses on their biological activity favoring the selection of highly potent drug candidates. These candidates, however, may have physical or chemical attributes that lead to unfavorable chemistry, manufacturing, and control (CMC) properties, such as low product titers, conformational and colloidal instabilities, or poor solubility

    更新日期:2020-07-13
  • A Phase 1 and pharmacokinetic study evaluating daily or weekly schedules of the humanized anti-GD2 antibody hu14.18K322A in recurrent/refractory solid tumors.
    mAbs (IF 4.634) Pub Date : 2020-07-09
    Michael W Bishop,Paul R Hutson,Jacquelyn A Hank,Paul M Sondel,Wayne L Furman,Michael M Meagher,Fariba Navid,Victor M Santana

    ABSTRACT Hu14.18K322A is a humanized anti-GD2 monoclonal antibody with a single point mutation that reduces complement-mediated cytotoxicity, with a maximum tolerated dose (MTD) of 60 mg/m2 daily for 4 days in children with recurrent/refractory neuroblastoma. We report additional results of a Phase 1 trial to determine the MTD and safety profile of hu14.18K322A in patients with osteosarcoma, and of

    更新日期:2020-07-09
  • An evaluation of instrument types for mass spectrometry-based multi-attribute analysis of biotherapeutics.
    mAbs (IF 4.634) Pub Date : 2020-07-09
    Zhongqi Zhang,Pik K Chan,Jason Richardson,Bhavana Shah

    ABSTRACT Multi-attribute methods (MAM), based on proteolytic digestion followed by liquid chromatography-mass spectrometry analysis of proteolytic peptides, have gained substantial attention in the biopharmaceutical industry for quantifying a variety of quality attributes for therapeutic proteins. Most MAM developed so far have been based on high-resolution mass spectrometers, due to their superb resolving

    更新日期:2020-07-09
  • Prevention of Fab-arm exchange and antibody reduction via stabilization of the IgG4 hinge region.
    mAbs (IF 4.634) Pub Date : 2020-07-07
    Michael W Handlogten,Li Peng,Elizabeth A Christian,Weichen Xu,Shihua Lin,Raghavan Venkat,William Dall'Acqua,Sanjeev Ahuja

    ABSTRACT IgG4s are dynamic molecules that undergo a process called Fab-arm exchange. Disulfide bonds between heavy chains are transiently reduced, resulting in half antibodies that reform intact antibodies with other IgG4 half antibodies. In vivo, therapeutic IgG4s can recombine with endogenous IgG4s, resulting in a heterogeneous mixture of bispecific antibodies. A related issue that can occur for

    更新日期:2020-07-07
  • Investigation of monoclonal antibody dimers in a final formulated drug by separation techniques coupled to native mass spectrometry.
    mAbs (IF 4.634) Pub Date : 2020-07-07
    G Rouby,N T Tran,Y Leblanc,M Taverna,N Bihoreau

    ABSTRACT Therapeutic monoclonal antibodies (mAbs) are highly complex proteins that must be exhaustively characterized according to the regulatory authorities' recommendations. MAbs display micro-heterogeneity mainly due to their post-translational modifications, but also to their susceptibility to chemical and physical degradations. Among these degradations, aggregation is quite frequent, initiated

    更新日期:2020-07-07
  • Ig-like ACE2 protein therapeutics: A revival in development during the COVID-19 pandemic.
    mAbs (IF 4.634) Pub Date : 2020-07-07
    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:2020-07-07
  • 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
  • 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