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  • Rabbits transgenic for human IgG genes recapitulating rabbit B-cell biology to generate human antibodies of high specificity and affinity
    mAbs (IF 4.634) Pub Date : 2020-11-24
    Francesca Ros; Sonja Offner; Stefan Klostermann; Irmgard Thorey; Helmut Niersbach; Sebastian Breuer; Grit Zarnt; Stefan Lorenz; Juergen Puels; Basile Siewe; Nicole Schueler; Tajana Dragicevic; Dominique Ostler; Imke Hansen-Wester; Valeria Lifke; Brigitte Kaluza; Klaus Kaluza; Wim van Schooten; Roland Buelow; Alain C Tissot; Josef Platzer

    ABSTRACT Transgenic animals incorporating human antibody genes are extremely attractive for drug development because they obviate subsequent antibody humanization procedures required for therapeutic translation. Transgenic platforms have previously been established using mice, but also more recently rats, chickens, and cows and are now in abundant use for drug development. However, rabbit-based antibody

    更新日期:2020-11-25
  • Diverse HIV-1 escape pathways from broadly neutralizing antibody PGDM1400 in humanized mice
    mAbs (IF 4.634) Pub Date : 2020-11-20
    Yme U. van der Velden; Julien Villaudy; Esther Siteur - van Rijnstra; Cynthia A. van der Linden; Monique A. Vink; Edith E. Schermer; Kees Weijer; Ben Berkhout; Rogier W. Sanders; Marit J. van Gils

    ABSTRACT Recent studies have shown the potential of broadly neutralizing antibodies (bnAbs) for HIV-1 treatment. One of the candidate antibodies moving into clinical trials is the bnAb PGDM1400. Here, we studied the therapeutic potency and escape pathways of bnAb PGDM1400 during monovalent therapy in human immune system (HIS) mice using the BG505, REJO, MJ4 and AMC008 virus isolates. PGDM1400 administered

    更新日期:2020-11-21
  • Selection and verification of antibodies against the cytoplasmic domain of M2 of influenza, a transmembrane protein
    mAbs (IF 4.634) Pub Date : 2020-11-18
    Nileena Velappan; Sofiya Micheva-Viteva; Samantha H. Adikari; Geoffrey S. Waldo; Antonietta M. Lillo; Andrew R.M. Bradbury

    ABSTRACT Interactions between the cytoplasmic domains of viral transmembrane proteins and host machinery often determine the outcome of viral infection. The M2 protein of influenza A has been identified as a key player in autophagy-mediated viral replication. Here, we describe the engineering and validation of an antibody specific for the cytoplasmic domain of the M2 protein. Through phage and yeast

    更新日期:2020-11-19
  • Discovery and characterization of a neutralizing pan-ELR+CXC chemokine monoclonal antibody
    mAbs (IF 4.634) Pub Date : 2020-11-13
    Jeffrey S. Boyles; Catherine B. Beidler; Beth A. Strifler; Daniel S. Girard; Zhanna Druzina; Jim D. Durbin; Michelle L. Swearingen; Linda N. Lee; Kristine Kikly; Sudhakar Chintharlapalli; Derrick R. Witcher

    ABSTRACT CXCR1 and CXCR2 signaling play a critical role in neutrophil migration, angiogenesis, and tumorigenesis and are therefore an attractive signaling axis to target in a variety of indications. In human, a total of seven chemokines signal through these receptors and comprise the ELR+CXC chemokine family, so named because of the conserved ELRCXC N-terminal motif. To fully antagonize CXCR1 and CXCR2

    更新日期:2020-11-13
  • Hiding in plain sight: structure and sequence analysis reveals the importance of the antibody DE loop for antibody-antigen binding
    mAbs (IF 4.634) Pub Date : 2020-11-12
    Simon P. Kelow; Jared Adolf-Bryfogle; Roland L. Dunbrack

    ABSTRACT Antibody variable domains contain “complementarity-determining regions” (CDRs), the loops that form the antigen binding site. CDRs1-3 are recognized as the canonical CDRs. However, a fourth loop sits adjacent to CDR1 and CDR2 and joins the D and E strands on the antibody v-type fold. This “DE loop” is usually treated as a framework region, even though mutations in the loop affect the conformation

    更新日期:2020-11-13
  • Impact of Fc N-linked glycans on in vivo clearance of an immunoglobulin G1 antibody produced by NS0 cell line
    mAbs (IF 4.634) Pub Date : 2020-11-10
    Jun Kim; Haibin Luo; Wendy White; William Rees; Raghavan Venkat; Methal Albarghouthi

    ABSTRACT The heterogeneity of glycosylation on therapeutic monoclonal antibodies (mAbs) may affect the safety and efficacy of these agents. In particular, glycans of nonhuman origin, such as galactose-alpha-1,3-galactose (gal-α-gal) and N-glycolylneuraminic acid (NGNA), in the Fc region of therapeutic mAbs produced from murine cell lines carry a risk of immunogenicity. Immunogenic glycan structures

    更新日期:2020-11-12
  • Vaccine-induced CD8 T cells are redirected with peptide-MHC class I-IgG antibody fusion proteins to eliminate tumor cells in vivo
    mAbs (IF 4.634) Pub Date : 2020-11-05
    Cornelia Fischer; Michael W. Munks; Ann B. Hill; Richard A. Kroczek; Stefan Bissinger; Verena Brand; Martina Schmittnaegel; Sabine Imhof-Jung; Eike Hoffmann; Frank Herting; Christian Klein; Hendrik Knoetgen

    ABSTRACT Simulating a viral infection in tumor cells is an attractive concept to eliminate tumor cells. We previously reported the molecular design and the in vitro potency of recombinant monoclonal antibodies fused to a virus-derived peptide MHC class I complex that bypass the peptide processing and MHC loading pathway and directly displays a viral peptide in an MHC class I complex on the tumor cell

    更新日期:2020-11-06
  • A monoclonal antibody with broad specificity for the ligands of insulin B:9-23 reactive T cells prevents spontaneous type 1 diabetes in mice
    mAbs (IF 4.634) Pub Date : 2020-11-05
    Joseph Ray Cepeda; Nitin S Sekhar; Junying Han; Wei Xiong; Ningyan Zhang; Liping Yu; Shaodong Dai; Howard W. Davidson; John W. Kappler; Zhiqiang An; Li Zhang

    ABSTRACT Activation of T cells specific for insulin B chain amino acids 9 to 23 (B:9–23) is essential for the initiation of type 1 diabetes (T1D) in non-obese diabetic mice. We previously reported that peptide/MHC complexes containing optimized B:9–23 mimotopes can activate most insulin-reactive pathogenic T cells. A monoclonal antibody (mAb287) targeting these complexes prevented disease in 30–50%

    更新日期:2020-11-06
  • Fully human anti-CD39 antibody potently inhibits ATPase activity in cancer cells via uncompetitive allosteric mechanism
    mAbs (IF 4.634) Pub Date : 2020-11-04
    Bradley N. Spatola; Alana G. Lerner; Clifford Wong; Tracy dela Cruz; Megan Welch; Wanchi Fung; Maria Kovalenko; Karolina Losenkova; Gennady G. Yegutkin; Courtney Beers; John Corbin; Vanessa B. Soros

    ABSTRACT The extracellular ATP/adenosine axis in the tumor microenvironment (TME) has emerged as an important immune-regulatory pathway. Nucleoside triphosphate diphosphohydrolase-1 (NTPDase1), otherwise known as CD39, is highly expressed in the TME, both on infiltrating immune cells and tumor cells across a broad set of cancer indications. CD39 processes pro-inflammatory extracellular ATP to ADP and

    更新日期:2020-11-04
  • Novel human monoclonal antibodies specific to the alternatively spliced domain D of Tenascin C efficiently target tumors in vivo
    mAbs (IF 4.634) Pub Date : 2020-11-02
    Lisa Nadal; Riccardo Corbellari; Alessandra Villa; Tobias Weiss; Michael Weller; Dario Neri; Roberto De Luca

    ABSTRACT Antibody-based delivery of bioactive molecules represents a promising strategy for the improvement of cancer immunotherapy. Here, we describe the generation and characterization of R6N, a novel fully human antibody specific to the alternatively spliced domain D of Tenascin C, which is highly expressed in the stroma of primary tumors and metastasis. The R6N antibody recognized its cognate tumor-associated

    更新日期:2020-11-03
  • CAR-J cells for antibody discovery and lead optimization of TCR-like immunoglobulins
    mAbs (IF 4.634) Pub Date : 2020-11-02
    Christian Jost; Diana Darowski; John Challier; Vesna Pulko; Lydia J Hanisch; Wei Xu; Ekkehard Mössner; Alexander Bujotzek; Stefan Klostermann; Pablo Umana; Roland E. Kontermann; Christian Klein

    ABSTRACT T-cell bispecific antibodies (TCBs) are a novel class of engineered immunoglobulins that unite monovalent binding to the T-cell receptor (TCR) CD3e chain and bivalent binding to tumor-associated antigens in order to recruit and activate T-cells for tumor cell killing. In vivo, T-cell activation is usually initiated via the interaction of the TCR with the peptide-HLA complex formed by the human

    更新日期:2020-11-03
  • Isolation of monoclonal antibodies from anti-synthetase syndrome patients and affinity maturation by recombination of independent somatic variants
    mAbs (IF 4.634) Pub Date : 2020-11-01
    Luke Burman; Yeeting E. Chong; Sherie Duncan; Anders Klaus; Kaitlyn Rauch; Kristina Hamel; Karine Hervé; Stephanie Pfaffen; David W. Collins; Kevin Heyries; Leslie Nangle; Carl Hansen; David J. King

    ABSTRACT The autoimmune disease known as Jo-1 positive anti-synthetase syndrome (ASS) is characterized by circulating antibody titers to histidyl-tRNA synthetase (HARS), which may play a role in modulating the non-canonical functions of HARS. Monoclonal antibodies to HARS were isolated by single-cell screening and sequencing from three Jo-1 positive ASS patients and shown to be of high affinity, covering

    更新日期:2020-11-02
  • Removal of variable domain N-linked glycosylation as a means to improve the homogeneity of HIV-1 broadly neutralizing antibodies
    mAbs (IF 4.634) Pub Date : 2020-10-30
    Gwo-Yu Chuang; Mangaiarkarasi Asokan; Vera B. Ivleva; Amarendra Pegu; Eun Sung Yang; Baoshan Zhang; Rajoshi Chaudhuri; Hui Geng; Bob C. Lin; Mark K. Louder; Krisha McKee; Sijy O’Dell; Hairong Wang; Tongqing Zhou; Nicole A. Doria-Rose; Lisa A. Kueltzo; Q. Paula Lei; John R. Mascola; Peter D. Kwong

    ABSTRACT Broadly neutralizing antibodies are showing promise in the treatment and prevention of HIV-1, with several now being evaluated clinically. Some lead clinical candidates, including antibodies CAP256-VRC26.25, N6, PGT121, and VRC07-523, have one or more N-linked glycosylation sequons in their variable domains (Fvs) from somatic hypermutation, and these glycans increase chemical heterogeneity

    更新日期:2020-10-30
  • Beyond affinity: selection of antibody variants with optimal biophysical properties and reduced immunogenicity from mammalian display libraries
    mAbs (IF 4.634) Pub Date : 2020-10-25
    Michael R. Dyson; Edward Masters; Deividas Pazeraitis; Rajika L. Perera; Johanna L. Syrjanen; Sachin Surade; Nels Thorsteinson; Kothai Parthiban; Philip C. Jones; Maheen Sattar; Gordana Wozniak-Knopp; Florian Rueker; Rachael Leah; John McCafferty

    ABSTRACT The early phase of protein drug development has traditionally focused on target binding properties leading to a desired mode of therapeutic action. As more protein therapeutics pass through the development pipeline; however, it is clear that non-optimal biophysical properties can emerge, particularly as proteins are formulated at high concentrations, causing aggregation or polyreactivity.

    更新日期:2020-10-30
  • Pharmacokinetics of novel Fc-engineered monoclonal and multispecific antibodies in cynomolgus monkeys and humanized FcRn transgenic mouse models
    mAbs (IF 4.634) Pub Date : 2020-10-20
    Delphine Valente; Christine Mauriac; Thorsten Schmidt; Ingo Focken; Jochen Beninga; Brian Mackness; Huawei Qiu; Pascale Vicat; Abdullah Kandira; Katarina Radošević; Srini Rao; John Darbyshire; Mostafa Kabiri

    ABSTRACT Monoclonal antibodies (mAbs) are among the fastest growing and most effective therapies for myriad diseases. Multispecific antibodies are an emerging class of novel therapeutics that can target more than one tumor- or immune-associated modulators per molecule. The combination of different binding affinities and target classes, such as soluble or membrane-bound antigens, within multispecific

    更新日期:2020-10-20
  • Cross-species/cross-modality physiologically based pharmacokinetics for biologics: 89Zr-labelled albumin-binding domain antibody GSK3128349 in humans
    mAbs (IF 4.634) Pub Date : 2020-10-19
    Armin Sepp; Mats Bergström; Marie Davies

    ABSTRACT Two-pore physiologically-based pharmacokinetics (PBPK) for biologics describes the tissue distribution and elimination kinetics of soluble proteins as a function of their hydrodynamic radius and the physiological properties of the organs. Whilst many studies have been performed in rodents to parameterize the PBPK framework in terms of organ-specific lymph flow rates, similar validation in

    更新日期:2020-10-19
  • Design of next-generation therapeutic IgG4 with improved manufacturability and bioanalytical characteristics
    mAbs (IF 4.634) Pub Date : 2020-10-12
    Zhiqiang Chen; Yueming Qian; Yuanli Song; Xuankuo Xu; Li Tao; Nesredin Mussa; Sanchayita Ghose; Zheng Jian Li

    ABSTRACT Manufacturability of immunoglobulin G4 (IgG4) antibodies from the Chemistry, Manufacture, and Controls (CMC) perspective has received little attention during early drug discovery. Despite the success of protein engineering in improving antibody biophysical properties, a clear gap still exists between rational design of IgG4 candidates and their manufacturing suitability. Here, we illustrate

    更新日期:2020-10-12
  • Optimization and kinetic modeling of interchain disulfide bond reoxidation of monoclonal antibodies in bioprocesses
    mAbs (IF 4.634) Pub Date : 2020-10-08
    Peifeng Tang; Zhijun Tan; Vivekh Ehamparanathan; Tingwei Ren; Laurel Hoffman; Cheng Du; Yuanli Song; Li Tao; Angela Lewandowski; Sanchayita Ghose; Zheng Jian Li; Shijie Liu

    ABSTRACT Disulfide bonds play a crucial role in folding and structural stabilization of monoclonal antibodies (mAbs). Disulfide bond reduction may happen during the mAb manufacturing process, resulting in low molecular weight species and possible failure to meet product specifications. Although many mitigation strategies have been developed to prevent disulfide reduction, to the best of our knowledge

    更新日期:2020-10-11
  • Functional humanization of immunoglobulin heavy constant gamma 1 Fc domain human FCGRT transgenic mice
    mAbs (IF 4.634) Pub Date : 2020-10-07
    Benjamin E. Low; Gregory J. Christianson; Emily Lowell; Wenning Qin; Michael V. Wiles

    ABSTRACT A major asset of many monoclonal antibody (mAb)-based biologics is their persistence in circulation. The MHC class I family Fc receptor, FCGRT, is primarily responsible for this extended pharmacokinetic behavior. Engagement of FCGRT with the crystallizable fragment (Fc) domain protects IgG from catabolic elimination, thereby extending the persistence and bioavailability of IgG and related

    更新日期:2020-10-07
  • On-column disulfide bond formation of monoclonal antibodies during Protein A chromatography eliminates low molecular weight species and rescues reduced antibodies
    mAbs (IF 4.634) Pub Date : 2020-10-04
    Zhijun Tan; Vivekh Ehamparanathan; Tingwei Ren; Peifeng Tang; Laurel Hoffman; June Kuang; Peiran Liu; Chao Huang; Cheng Du; Li Tao; Letha Chemmalil; Angela Lewandowski; Sanchayita Ghose; Zheng Jian Li; Shijie Liu

    ABSTRACT Disulfide bond reduction, which commonly occurs during monoclonal antibody (mAb) manufacturing processes, can result in a drug substance with high levels of low molecular weight (LMW) species that may fail release specifications because the drug’s safety and the efficiency may be affected by the presence of this material. We previously studied disulfide reoxidation of mAbs and demonstrated

    更新日期:2020-10-05
  • A minimal physiologically based pharmacokinetic model to characterize colon TNF suppression and treatment effects of an anti-TNF monoclonal antibody in a mouse inflammatory bowel disease model.
    mAbs (IF 4.634) Pub Date : 2020-09-24
    Songmao Zheng,Jin Niu,Brian Geist,Damien Fink,Zhenhua Xu,Honghui Zhou,Weirong Wang

    Biotherapeutic drugs against tumor necrosis factor (TNF) are effective treatments for moderate to severe inflammatory bowel disease (IBD). Here, we evaluated CNTO 5048, an antimurine TNF surrogate monoclonal antibody (mAb), in a CD45RBhigh adoptive T cell transfer mouse colitis model, which allows examination of the early immunological events associated with gut inflammation and the therapeutic effects

    更新日期:2020-09-24
  • 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