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Thorsten Krause, Niels Röckendorf, Karoline I Gaede, Katrin Ramaker, Heike Sinnecker, Andreas Frey
In chronic inflammatory airway diseases, mucins display disease-related alterations in quantity, composition and glycosylation. This opens the possibility to diagnose and monitor inflammatory airway disorders and their exacerbation based on mucin properties. For such an approach to be reasonably versatile and diagnostically meaningful, the mucin of interest must be captured in a reliable, patient-independent way. To identify appropriate mucin-specific reagents, we tested anti-mucin antibodies on mucin-content-standardized, human bronchoalveolar lavage fluid samples in immunoblot assays...
December 2, 2016: MAbs
Patrick M Glassman, Joseph P Balthasar
Many clinically approved and investigational monoclonal antibody (mAb)-based therapeutics are directed against proteins located in the systemic circulation, including cytokines, growth factors, lymphocyte proteins, and shed antigens. Interaction between mAb and target may lead to non-linear pharmacokinetics (PK), characterized by rapid, target-mediated elimination. Several groups have reported that determinants of target-mediated elimination could include mAb-target binding, target expression, and target turnover...
November 28, 2016: MAbs
Laurent Magnenat, Angelo Palmese, Christèle Fremaux, Fabio D'Amici, Mariagrazia Terlizzese, Mara Rossi, Laurent Chevalet
Biosimilars are biological products that are highly similar to existing products approved by health authorities. Demonstration of similarity starts with the comprehensive analysis of the reference product and its proposed biosimilar at the physicochemical and functional levels. Here, we report the results of a comparative analysis of a proposed biosimilar adalimumab MSB11022 and its reference product, Humira®. Three batches of MSB11022 and up to 23 batches of Humira® were analyzed by a set of state-of-the-art orthogonal methods...
November 17, 2016: MAbs
Melissa L Geddie, Neeraj Kohli, Dmitri B Kirpotin, Maja Razlog, Yang Jiao, Tad Kornaga, Rachel Rennard, Lihui Xu, Birgit Schoerberl, James D Marks, Daryl C Drummond, Alexey A Lugovskoy
Antibody-targeted nanoparticles have great promise as anti-cancer drugs; however, substantial developmental challenges of antibody modules prevent many candidates from reaching the clinic. Here, we describe a robust strategy for developing an EphA2-targeting antibody fragment for immunoliposomal drug delivery. A highly bioactive single-chain variable fragment (scFv) was engineered to overcome developmental liabilities, including low thermostability and weak binding to affinity purification resins. Improved thermostability was achieved by modifying the framework of the scFv, and complementarity-determining region (CDR)-H2 was modified to increase binding to protein A resins...
November 17, 2016: MAbs
Ping Tsui, Daniel R Higazi, Yanli Wu, Rebecca Dunmore, Emilie Solier, Toyin Kasali, Nicholas J Bond, Catherine Huntington, Alan Carruthers, John Hood, M Jack Borrok, Arnita Barnes, Keith Rickert, Sandrina Phipps, Lena Shirinian, Jie Zhu, Michael A Bowen, William Dall'Acqua, Lynne A Murray
Excessive transforming growth factor (TGF)-β is associated with pro-fibrotic responses in lung disease, yet it also plays essential roles in tissue homeostasis and autoimmunity. Therefore, selective inhibition of excessive and aberrant integrin-mediated TGF-β activation via targeting the alpha-v family of integrins is being pursued as a therapeutic strategy for chronic lung diseases, to mitigate any potential safety concerns with global TGF-β inhibition. In this work, we reveal a novel mechanism of inhibiting TGF-β activation utilized by an αvβ8 targeting antibody, 37E1B5...
November 11, 2016: MAbs
Charlotte M Deane, Maximiliano Vásquez
No abstract text is available yet for this article.
November 7, 2016: MAbs
Karen Lam, Conrad Chan, Raymond M Reilly
We previously reported that microSPECT/CT imaging with (111)In-labeled pertuzumab detected decreased HER2 expression in human breast cancer (BC) xenografts in athymic mice associated with response to treatment with trastuzumab (Herceptin). Our aim was to extend these results to PET/CT by constructing F(ab')2 of pertuzumab modified with NOTA chelators for complexing (64)Cu. The effect of the administered mass (5-200 µg) of (64)Cu-NOTA-pertuzumab F(ab')2 was studied in NOD/SCID mice engrafted with HER2-positive SK-OV-3 human ovarian cancer xenografts...
November 4, 2016: MAbs
Jérémy Pottier, Romane Chastang, Christophe Dumet, Hervé Watier
In the context of a possible revision of the International Nonproprietary Names (INN) system of recombinant monoclonal antibodies, which is saturated, we propose several avenues of reflection driven by the primary goal of the INN, information of health-care professionals. Clinical considerations argue for an abandon of the substems A (target category) and B (origin category), which lengthen the INN without real added-value. On the contrary, new substems or suffixes are required to alert on the absence/presence of an Fc portion and/or multispecificity, which are essential from a pharmacological point of view...
November 3, 2016: MAbs
(no author information available yet)
No abstract text is available yet for this article.
November 3, 2016: MAbs
(no author information available yet)
No abstract text is available yet for this article.
October 28, 2016: MAbs
Katharine D Grugan, Keri Dorn, Stephen W Jarantow, Barbara S Bushey, Jose R Pardinas, Sylvie Laquerre, Sheri L Moores, Mark Chiu
Epidermal growth factor receptor (EGFR) mutant non-small cell lung cancers acquire resistance to EGFR tyrosine kinase inhibitors through multiple mechanisms including c-Met receptor pathway activation. We generated a bispecific antibody targeting EGFR and c-Met (JNJ-61186372) demonstrating anti-tumor activity in wild-type and mutant EGFR settings with c-Met pathway activation. JNJ-61186372 was engineered with low fucosylation (<10%), resulting in enhanced antibody-dependent cell-mediated cytotoxicity and FcyRIIIa binding...
October 27, 2016: MAbs
Martin J Scott, Jennifer A Lee, Matthew S Wake, Kelly V Batt, Trevor A Wattam, Ian D Hiles, Thil D Batuwangala, Claire I Ashman, Michael Steward
Bispecific antibodies (BsAbs) are emerging as an important class of biopharmaceutical. The majority of BsAbs are created from conventional antibodies or fragments engineered into more complex configurations. A recurring challenge in their development, however, is the identification of components that are optimised for inclusion in the final format in order to deliver both efficacy and robust biophysical properties. Using a modular BsAb format, the mAb-dAb, we assessed whether an 'in-format' screening approach, designed to select format-compatible domain antibodies, could expedite lead discovery...
October 27, 2016: MAbs
Timothy J Egan, Dania Diem, Richard Weldon, Tessa Neumann, Sebastian Meyer, David M Urech
Multispecific antibody formats provide a promising platform for the development of novel therapeutic concepts that could facilitate the generation of safer, more effective pharmaceuticals. However, the production and use of such antibody-based multispecifics is often made complicated by: 1) the instability of the antibody fragments of which they consist, 2) undesired inter-subunit associations, and 3) the need to include recombinant heterodimerization domains that confer distribution-impairing bulk or enhance immunogenicity...
October 27, 2016: MAbs
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
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