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Janice M Reichert
No abstract text is available yet for this article.
October 20, 2016: MAbs
Arvind Sivasubramanian, Patricia Estep, Heather Lynaugh, Yao Yu, Adam Miles, Josh Eckman, Kevin Schutz, Crystal Piffath, Nadthakarn Boland, Rebecca Hurley Niles, Stéphanie Durand, Todd Boland, Maximiliano Vásquez, Yingda Xu, Yasmina Abdiche
Successful discovery of therapeutic antibodies hinges on the identification of appropriate affinity binders targeting a diversity of molecular epitopes presented by the antigen. Antibody campaigns that yield such broad "epitope coverage" increase the likelihood of identifying candidates with the desired biological functions. Accordingly, epitope binning assays are employed in the early discovery stages to partition antibodies into epitope families or "bins" and prioritize leads for further characterization and optimization...
October 17, 2016: MAbs
(no author information available yet)
No abstract text is available yet for this article.
September 29, 2016: MAbs
Whitney Shatz, Domingos Ng, George Dutina, Athena W Wong, Diana Ronai Dunshee, Junichiro Sonoda, Amy Shen, Justin M Scheer
Bispecific antibodies have shown promise in the clinic as medicines with novel mechanisms of action. Lack of efficient production of bispecific IgGs, however, has limited their rapid advancement. Here, we describe a single-reactor process using mammalian cell co-culture production to efficiently produce a bispecific IgG with four distinct polypeptide chains without the need for parallel processing of each half-antibody or additional framework mutations. This method resembles a conventional process, and the quality and yield of the monoclonal antibodies are equal to those produced using parallel processing methods...
September 28, 2016: MAbs
Michael Dobosz, Ute Haupt, Werner Scheuer
Preclinical efficacy studies of antibodies targeting a tumor-associated antigen are only justified when the expression of the relevant antigen has been demonstrated. Conventionally, antigen expression level is examined by immunohistochemistry of formalin-fixed paraffin-embedded tumor tissue section. This method represents the diagnostic "gold standard" for tumor target evaluation, but is affected by a number of factors, such as epitope masking and insufficient antigen retrieval. As a consequence, variances and discrepancies in histological staining results can occur, which may influence decision-making and therapeutic outcome...
September 23, 2016: MAbs
Oksana Tyshchuk, Hans Rainer Völger, Claudia Ferrara, Patrick Bulau, Hans Koll, Michael Mølhøj
Molecular mass determination by electrospray ionization mass spectrometry of a recombinant IgG-based fusion protein (mAb1-F) produced in human embryonic kidney (HEK) cells demonstrated the presence of a dominant +79 Da product variant. Using LC-MS tryptic peptide mapping analysis and collision-induced dissociation (CID) and electron-transfer/higher-energy collision dissociation fragmentations, the modification was localized to the C-terminal serine residue of a glycine-serine linker [(G4S)2] of a fused heavy chain containing in total two (G4S)2-linkers...
September 23, 2016: MAbs
Sihem Ait-Oudhia, Meric Ayse Ovacik, Donald E Mager
Pharmacokinetic (PK) and pharmacodynamic (PD) models seek to describe the temporal pattern of drug exposures and their associated pharmacological effects produced at micro- and macro-scales of organization. Antibody-based drugs have been developed for a large variety of diseases, with effects exhibited through a comprehensive range of mechanisms of action. Mechanism-based PK/PD and systems pharmacology models can play a major role in elucidating and integrating complex antibody pharmacological properties, such as nonlinear disposition and dynamical intracellular signaling pathways triggered by ligation to their cognate targets...
September 23, 2016: MAbs
Patricia M Legler, Jaimee R Compton, Martha L Hale, George P Anderson, Mark A Olson, Charles B Millard, Ellen R Goldman
Ricin is an A-B ribosome inactivating protein (RIP) toxin composed of an A-chain subunit (RTA) that contains a catalytic N-glycosidase and a B-chain (RTB) lectin domain that binds cell surface glycans. Ricin exploits retrograde transport to enter into the Golgi and the endoplasmic reticulum, and then dislocates into the cytoplasm where it can reach its substrate, the ribosomal RNA. A subset of isolated antibodies (Abs) raised against the RTA subunit protect against ricin intoxication, and RTA-based vaccine immunogens have been shown to provide long-lasting protective immunity against the holotoxin...
September 23, 2016: MAbs
Chenguang Zhou, Sophie Lehar, Johnny Gutierrez, Carrie M Rosenberger, Nina Ljumanovic, Jason Dinoso, Neelima Koppada, Kyu Hong, Amos Baruch, Montserrat Carrasco-Triguero, Ola Saad, Sanjeev Mariathasan, Amrita V Kamath
DSTA4637A, a novel THIOMAB™ antibody antibiotic conjugate (TAC) against Staphylococcus aureus (S. aureus), is currently being investigated as a potential therapy against S. aureus infections. Structurally, TAC is composed of an anti-S. aureus antibody linked to a potent antibiotic, dmDNA31. The goal of the current study was to characterize the pharmacokinetics (PK) of TAC in mice, assess the effect of S. aureus infection on its PK, and evaluate its pharmacodynamics (PD) by measuring the bacterial load in various organs at different timepoints following TAC treatment...
September 21, 2016: MAbs
James R Apgar, Michelle Mader, Rita Agostinelli, Susan Benard, Peter Bialek, Mark Johnson, Yijie Gao, Mark Krebs, Jane Owens, Kevin Parris, Michael St Andre, Kris Svenson, Carl Morris, Lioudmila Tchistiakova
Antibodies are an important class of biotherapeutics that offer specificity to their antigen, long half-life, effector function interaction and good manufacturability. The immunogenicity of non-human-derived antibodies, which can be a major limitation to development, has been partially overcome by humanization through complementarity-determining region (CDR) grafting onto human acceptor frameworks. The retention of foreign content in the CDR regions, however, is still a potential immunogenic liability. Here, we describe the humanization of an anti-myostatin antibody utilizing a 2-step process of traditional CDR-grafting onto a human acceptor framework, followed by a structure-guided approach to further reduce the murine content of CDR-grafted antibodies...
September 13, 2016: MAbs
Brian Kelley
No abstract text is available yet for this article.
September 12, 2016: MAbs
Tetyana Dashivets, Jan Stracke, Stefan Dengl, Alexander Knaupp, Jan Pollmann, Johannes Buchner, Tilman Schlothauer
Therapeutic antibodies can undergo a variety of chemical modification reactions in vitro. Depending on the site of modification, either antigen binding or Fc-mediated functions can be affected. Oxidation of tryptophan residues is one of the post-translational modifications leading to altered antibody functionality. In this study, we examined the structural and functional properties of a therapeutic antibody construct and 2 affinity matured variants thereof. Two of the 3 antibodies carry an oxidation-prone tryptophan residue in the complementarity-determining region of the VL domain...
September 9, 2016: MAbs
Yiyuan Yin, Guanghui Han, Jianhui Zhou, Michael Dillon, Luke McCarty, Lou Gavino, Diego Ellerman, Christoph Spiess, Wendy Sandoval, Paul J Carter
Bispecific IgG are heterotetramers comprising 2 pairs of heavy and light chains. Co-expression of the 4 component chains in a single host cell typically yields the desired bispecific IgG plus up to 9 additional incorrect chain pairings. Several protein engineering strategies have been reported to facilitate the heterodimerization of antibody heavy chains or cognate pairing of antibody heavy and light chains. These technologies have been used to direct the efficient assembly of bispecific IgG in single host cells and minimize unwanted chain pairings...
September 9, 2016: MAbs
Ryan L Kelly, Yao Yu, Tingwan Sun, Isabelle Caffry, Heather Lynaugh, Michael Brown, Tushar Jain, Yingda Xu, K Dane Wittrup
The importance of the neonatal Fc receptor (FcRn) in extending the serum half-life of monoclonal antibodies (mAbs) is well demonstrated, and has led to the development of multiple engineering approaches designed to alter Fc interactions with FcRn. Recent reports have additionally highlighted the effect of nonspecific interactions on antibody pharmacokinetics (PK), suggesting an FcRn-independent mechanism for mAb clearance. In this report we examine a case study of two anti-interleukin-12/23 antibodies, ustekinumab and briakinumab, which share the same target and Fc, but differ in variable region sequences...
September 9, 2016: MAbs
Li Peng, Kimberly Cook, Linda Xu, Li Cheng, Melissa Damschroder, Changshou Gao, Herren Wu, William F Dall'Acqua
Inhibitors of tumor necrosis factor-α converting enzyme (TACE) have potential as therapeutics for various diseases. Many small molecule inhibitors, however, exhibit poor specificity profiles because they target the highly conserved catalytic cleft of TACE. We report for the first time the molecular interaction of a highly specific anti-TACE antagonistic antibody (MEDI3622). We characterized the binding of MEDI3622 using mutagenesis, as well as structural modeling and docking approaches. We show that MEDI3622 recognizes a unique surface loop of sIVa-sIVb β-hairpin on TACE M-domain, but does not interact with the conserved catalytic cleft or its nearby regions...
September 9, 2016: MAbs
Yi Wang, Xiaojuan Li, Yan-Hui Liu, Daisy Richardson, Huijuan Li, Mohammed Shameem, Xiaoyu Yang
Monoclonal antibodies are subjected to a wide variety of post-translational modifications (PTMs) that cause structural heterogeneity. Characterization and control of these modifications or quality attributes are critical to ensure antibody quality and to define any potential effects on the ultimate safety and potency of antibody therapeutics. The biopharmaceutical industry currently uses numerous tools to analyze these quality attributes individually, which requires substantial time and resources. Here, we report a simple and ultrafast bottom-up liquid chromatography-mass spectrometry (uLC-MS) method with 5 min tryptic digestion to simultaneously analyze multiple modifications, including oxidation, deamidation, isomerization, glycation, glycosylation, and N-terminal pyro-glutamate formation, which can occur during antibody production in mammalian cell culture, during purification and/or on storage...
September 6, 2016: MAbs
Maria Myzithras, Tammy Bigwarfe, Hua Li, Erica Waltz, Jennifer Ahlberg, Craig Giragossian, Simon Roberts
Prior to clinical studies, the pharmacokinetics (PK) of antibody-based therapeutics are characterized in preclinical species; however, those species can elicit immunogenic responses that can lead to an inaccurate estimation of PK parameters. Immunodeficient (SCID) transgenic hFcRn and C57BL/6 mice were used to characterize the PK of three antibodies that were previously shown to be immunogenic in mice and cynomolgus monkeys. Four mouse strains, Tg32 hFcRn SCID, Tg32 hFcRn, SCID and C57BL/6, were administered adalimumab (Humira®), mAbX and mAbX-YTE at 1 mg/kg, and in SCID strains there was no incidence of immunogenicity...
September 6, 2016: MAbs
In Young Park, Pratim Chowdhury, Durga Nand Tripathi, Reid T Powell, Ruhee Dere, Esteban A Terzo, W Kimryn Rathmell, Cheryl Lyn Walker
Posttranslational modifications (PTMs) on microtubules differentiate these cytoskeletal elements for a variety of cellular functions. We recently identified SETD2 as a dual-function histone and microtubule methyltransferase, and methylation as a new microtubule PTM that occurs on lysine 40 of α-tubulin, which is trimethylated (α-TubK40me3) by SETD2. In the course of these studies, we generated polyclonal (α-TubK40me3 pAb) and monoclonal (α-TubK40me3 mAb) antibodies to a methylated α-tubulin peptide (GQMPSD-Kme3-TIGGGDC)...
September 3, 2016: MAbs
Jenny Calow, Anna-Janina Behrens, Sonja Mader, Ulrike Bockau, Weston B Struwe, David J Harvey, Kai U Cormann, Marc M Nowaczyk, Karin Loser, Daniel Schinor, Marcus W W Hartmann, Max Crispin
Antibody glycosylation is a key parameter in the optimization of antibody therapeutics. Here, we describe the production of the anti-cancer monoclonal antibody rituximab in the unicellular ciliate, Tetrahymena thermophila. The resulting antibody demonstrated enhanced antibody-dependent cell-mediated cytotoxicity, which we attribute to unusual N-linked glycosylation. Detailed chromatographic and mass spectrometric analysis revealed afucosylated, oligomannose-type glycans, which, as a whole, displayed isomeric structures that deviate from the typical human counterparts, but whose branches were equivalent to fragments of metabolic intermediates observed in human glycoproteins...
September 3, 2016: MAbs
Annamaria Sandomenico, Annalia Focà, Luca Sanguigno, Andrea Caporale, Giuseppina Focà, Angelica Pignalosa, Giusy Corvino, Angela Caragnano, Antonio Paolo Beltrami, Giulia Antoniali, Gianluca Tell, Antonio Leonardi, Menotti Ruvo
Post-translational modifications (PTMs) strongly influence the structure and function of proteins. Lysine side chain acetylation is one of the most widespread PTMs, and it plays a major role in several physiological and pathological mechanisms. Protein acetylation may be detected by mass spectrometry (MS), but the use of monoclonal antibodies (mAbs) is a useful and cheaper option. Here, we explored the feasibility of generating mAbs against single or multiple acetylations within the context of a specific sequence...
August 25, 2016: MAbs
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