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https://www.readbyqxmd.com/read/29239690/antibody-drug-conjugates-design-and-development-for-therapy-and-imaging-in-and-beyond-cancer-labex-mabimprove-industrial-workshop-july-27-28-2017-tours-france
#1
Camille Martin, Claire Kizlik-Masson, André Pèlegrin, Hervé Watier, Marie-Claude Viaud-Massuard, Nicolas Joubert
The annual "Antibody Industrial Symposium", co organized by LabEx MAbImprove, MabDesign and Polepharma, was held in Tours, France on June 27-28, 2017. The focus was on antibody-drug-conjugates (ADCs), new entities which realize the hope of Paul Ehrlich's magic bullet. ADCs result from the bioconjugation of a highly cytotoxic drug to a selective monoclonal antibody, which acts as a vector. Building on knowledge gained during the development of three approved ADCs, brentuximab vedotin (Adcetris®), ado trastuzumab emtansine (Kadcyla®) and inotuzumab ozogamicin (Besponsa®), and the many ADCs in development, this meeting addressed strategies and the latest innovations in the field from fundamental research to manufacturing...
December 14, 2017: MAbs
https://www.readbyqxmd.com/read/29227213/productive-common-light-chain-libraries-yield-diverse-panels-of-high-affinity-bispecific-antibodies
#2
Thomas Van Blarcom, Kevin Lindquist, Zea Melton, Wai Ling Cheung, Chris Wagstrom, Dan McDonough, Cendy Valle Oseguera, Sheng Ding, Andrea Rossi, Shobha Potluri, Purnima Sundar, Steven Pitts, Marina Sirota, Meri Galindo Casas, Yu Yan, Jeffrey Jones, Zygy Roe-Zurz, Surabhi Srivatsa Srinivasan, Wenwu Zhai, Jaume Pons, Arvind Rajpal, Javier Chaparro-Riggers
The commercial success of bispecific antibodies generally has been hindered by the complexities associated with generating appropriate molecules for both research scale and large scale manufacturing purposes. Bispecific IgG (BsIgG) based on two antibodies that use an identical common light chain can be combined with a minimal set of Fc mutations to drive heavy chain heterodimerization in order to address these challenges. However, the facile generation of common light chain antibodies with properties similar to traditional monoclonal antibodies has not been demonstrated and they have only been used sparingly...
December 11, 2017: MAbs
https://www.readbyqxmd.com/read/29200314/assessment-of-structural-and-functional-similarity-of-biosimilar-products-rituximab-as-a-case-study
#3
Neh Nupur, Nidhi Chhabra, Rozaleen Dash, Anurag S Rathore
Biosimilars are products that are similar in terms of quality, safety, and efficacy to an already licensed reference/ innovator product and are expected to offer improved affordability. The most significant source of reduction in the cost of development of a biosimilar is the reduced clinical examination that it is expected to undergo as compared to the innovator product. However, this clinical relief is predicated on the assumption that there is analytical similarity between the biosimilar and the innovator product...
December 4, 2017: MAbs
https://www.readbyqxmd.com/read/29190188/biomeasures-and-mechanistic-modeling-highlight-pk-pd-risks-for-a-monoclonal-antibody-targeting-fn14-in-kidney-disease
#4
Xiaoying Chen, Vahid Farrokhi, Pratap Singh, Mireia Fernandez Ocana, Jenil Patel, Lih-Ling Lin, Hendrik Neubert, Joanne Brodfuehrer
Discovery of the upregulation of fibroblast growth factor-inducible-14 (Fn14) receptor following tissue injury has prompted investigation into biotherapeutic targeting of the Fn14 receptor for the treatment of conditions such as chronic kidney diseases. In the development of monoclonal antibody (mAb) therapeutics, there is an increasing trend to use biomeasures combined with mechanistic pharmacokinetic/pharmacodynamic (PK/PD) modeling to enable decision making in early discovery. With the aim of guiding preclinical efforts on designing an antibody with optimized properties, we developed a mechanistic site-of-action (SoA) PK/PD model for human application...
November 30, 2017: MAbs
https://www.readbyqxmd.com/read/29185848/monoclonal-antibodies-targeting-the-disintegrin-like-domain-of-adamdec1-modulates-the-proteolytic-activity-and-enables-quantification-of-adamdec1-protein-in-human-plasma
#5
Jacob Lund, Anne Mette Elimar Bitsch, Morten Grønbech Rasch, Mari Enoksson, Linda Troeberg, Hideaki Nagase, Mette Loftager, Michael Toft Overgaard, Helle Heibroch Petersen
Decysin-1 (ADAMDEC1) is an orphan ADAM-like metalloprotease with unknown biological function and a short domain structure. ADAMDEC1 mRNA has previously been demonstrated primarily in macrophages and mature dendritic cells. Here, we generated monoclonal antibodies (mAbs) against the mature ADAMDEC1 protein, as well as mAbs specific for the ADAMDEC1 pro-form, enabling further investigations of the metalloprotease. The generated mAbs bind ADAMDEC1 with varying affinity and represent at least six different epitope bins...
November 29, 2017: MAbs
https://www.readbyqxmd.com/read/29182455/isolation-of-blood-brain-barrier-crossing-antibodies-from-a-phage-display-library-by-competitive-elution-and-their-ability-to-penetrate-the-central-nervous-system
#6
George Thom, Jon Hatcher, Arron Hearn, Judy Paterson, Natalia Rodrigo, Arthur Beljeana Ian Gurrell, Carl Webster
The blood-brain barrier (BBB) is a formidable obstacle for delivery of biologic therapeutics to central nervous system (CNS) targets. Whilst the BBB prevents passage of the vast majority of molecules, it also selectively transports a wide variety of molecules required to maintain brain homeostasis. Receptor-mediated transcytosis is one example of a macromolecule transport system that is employed by cells of the BBB to supply essential proteins to the brain and which can be utilized to deliver biologic payloads, such as antibodies, across the BBB...
November 28, 2017: MAbs
https://www.readbyqxmd.com/read/29182441/elimination-of-tumor-by-cd47-pd-l1-dual-targeting-fusion-protein-that-engages-innate-and-adaptive-immune-responses
#7
Boning Liu, Huaizu Guo, Jin Xu, Ting Qin, Qingcheng Guo, Nana Gu, Dapeng Zhang, Weizhu Qian, Jianxin Dai, Sheng Hou, Hao Wang, Yajun Guo
The host immune system generally serves as a barrier against tumor formation. Programmed death-ligand 1 (PD-L1) is a critical "don't find me" signal to the adaptive immune system, whereas CD47 transmits an anti-phagocytic signal, known as the "don't eat me" signal, to the innate immune system. These and similar immune checkpoints are often overexpressed on human tumors. Thus, dual targeting both innate and adaptive immune checkpoints would likely maximize anti-tumor therapeutic effect and elicit more durable responses...
November 28, 2017: MAbs
https://www.readbyqxmd.com/read/29182427/note-of-appreciation-to-reviewers
#8
Janice M Reichert
No abstract text is available yet for this article.
November 28, 2017: MAbs
https://www.readbyqxmd.com/read/29173063/development-of-a-pre-glycoengineered-cho-k1-host-cell-line-for-the-expression-of-antibodies-with-enhanced-fc-mediated-effector-function
#9
Oliver Popp, Samuel Moser, Jörg Zielonka, Petra Rüger, Silke Hansen, Oliver Plöttner
Novel biotherapeutic glycoproteins, like recombinant monoclonal antibodies (mAbs) are widely used for the treatment of numerous diseases. The N-glycans attached to the constant region of an antibody have been demonstrated to be crucial for the biological efficacy. Even minor modifications of the N-glycan structure can dictate the potency of IgG effector functions such as the antibody-dependent cell-mediated cytotoxicity (ADCC) and complement-dependent cytotoxicity (CDC). Here, we present the development of a glycoengineered CHO-K1 host cell line (HCL), stably expressing β1,4-N-Acetylglucoseaminyltransferase III (GnT-III) and α-mannosidase II (Man-II), for the expression of a-fucosylated antibodies with enhanced Fc-mediated effector function...
November 27, 2017: MAbs
https://www.readbyqxmd.com/read/29173039/engineered-aglycosylated-full-length-igg-fc-variants-exhibiting-improved-fc%C3%AE-riiia-binding-and-tumor-cell-clearance
#10
Migyeong Jo, Hyeong Sun Kwon, Kwang-Hoon Lee, Ji Chul Lee, Sang Taek Jung
FcγRIIIa, which is predominantly expressed on the surface of natural killer cells, plays a key role in antibody-dependent cell-mediated cytotoxicity (ADCC), a major effector function of therapeutic IgG antibodies that results in the death of aberrant cells. Despite the potential uses of aglycosylated IgG antibodies, which can be easily produced in bacteria and do not have complicated glycan heterogeneity issues, they show negligible binding to FcγRIIIa and abolish the activation of immune leukocytes for tumor cell clearance, in sharp contrast to most glycosylated IgG antibodies used in the clinical setting...
November 27, 2017: MAbs
https://www.readbyqxmd.com/read/29135326/hydrogen-deuterium-exchange-mass-spectrometry-and-computational-modeling-reveal-a-discontinuous-epitope-of-an-antibody-tl1a-interaction
#11
Richard Y-C Huang, Stanley R Krystek, Nathan Felix, Robert F Graziano, Mohan Srinivasan, Achal Pashine, Guodong Chen
TL1A, a tumor necrosis factor-like cytokine, is a ligand for the death domain receptor DR3. TL1A, upon binding to DR3, can stimulate lymphocytes and trigger secretion of proinflammatory cytokines. Therefore, blockade of TL1A/DR3 interaction may be a potential therapeutic strategy for autoimmune and inflammatory diseases. Recently, the anti-TL1A monoclonal antibody 1 (mAb1) with a strong potency in blocking the TL1A/DR3 interaction was identified. Here, we report on the use of hydrogen/deuterium exchange mass spectrometry (HDX-MS) to obtain molecular-level details of mAb1's binding epitope on TL1A...
November 14, 2017: MAbs
https://www.readbyqxmd.com/read/29120699/tolerability-response-and-outcome-of-high-risk-neuroblastoma-patients-treated-with-long-term-infusion-of-anti-gd2-antibody-ch14-18-cho
#12
Ina Mueller, Karoline Ehlert, Stefanie Endres, Lena Pill, Nikolai Siebert, Silke Kietz, Penelope Brock, Alberto Garaventa, Dominique Valteau-Couanet, Evelyne Janzek, Norbert Hosten, Andreas Zinke, Winfried Barthlen, Emine Varol, Hans Loibner, Ruth Ladenstein, Holger N Lode
Immunotherapy with short term infusion (STI) of monoclonal anti-GD2 antibody (mAb) ch14.18 (4 × 25mg/m(2)/d; 8-20h) in combination with cytokines and 13-cis retinoic acid (RA) prolonged survival in high-risk neuroblastoma (NB) patients. Here, we investigated long-term infusion (LTI) of ch14.18 produced in Chinese hamster ovary cells (ch14.18/CHO; 10 × 10mg/m(2); 24h) in combination with subcutaneous (s.c.) interleukin-2 (IL-2) in a single center program and report clinical response, toxicity and survival...
November 9, 2017: MAbs
https://www.readbyqxmd.com/read/29120697/enhancing-antibody-patent-protection-using-epitope-mapping-information
#13
Xiaoxiang Deng, Ulrich Storz, Benjamin J Doranz
As the $100B therapeutic monoclonal antibody (mAb) market continues to grow, developers of therapeutic mAbs increasingly face the need to strengthen patent protection of their products and enforce their patents in courts. In view of changes in the patent law landscape, patent applications are strategically using information on the precise binding sites of their mAbs, i.e., the epitopes, to support patent novelty, non-obviousness, subject matter, and a tightened written description requirement for broad genus antibody claims...
November 9, 2017: MAbs
https://www.readbyqxmd.com/read/29035675/practical-considerations-in-clinical-strategy-to-support-the-development-of-injectable-drug-device-combination-products-for-biologics
#14
Zhaoyang Li, Rachael Easton
The development of an injectable drug-device combination (DDC) product for biologics is an intricate and evolving process that requires substantial investments of time and money. Consequently, the commercial dosage form(s) or presentation(s) are often not ready when pivotal trials commence, and it is common to have drug product changes (manufacturing process or presentation) during clinical development. A scientifically sound and robust bridging strategy is required in order to introduce these changes into the clinic safely...
October 16, 2017: MAbs
https://www.readbyqxmd.com/read/29035625/chickens-with-humanized-immunoglobulin-genes-generate-antibodies-with-high-affinity-and-broad-epitope-coverage-to-conserved-targets
#15
Kathryn H Ching, Ellen J Collarini, Yasmina N Abdiche, Daniel Bedinger, Darlene Pedersen, Shelley Izquierdo, Rian Harriman, Lei Zhu, Robert J Etches, Marie-Cecile van de Lavoir, William D Harriman, Philip A Leighton
Transgenic animal platforms for the discovery of human monoclonal antibodies have been developed in mice, rats, rabbits and cows. The immune response to human proteins is limited in these animals by their tolerance to mammalian-conserved epitopes. To expand the range of epitopes that are accessible, we have chosen an animal host that is less phylogenetically related to humans. Specifically, we generated transgenic chickens expressing antibodies from immunoglobulin heavy and light chain loci containing human variable regions and chicken constant regions...
October 16, 2017: MAbs
https://www.readbyqxmd.com/read/29035619/personalized-medicine-with-biologics-for-severe-type-2-asthma-current-status-and-future-prospects
#16
Marie Godar, Christophe Blanchetot, Hans de Haard, Bart N Lambrecht, Guy Brusselle
Asthma affects more than 300 million people worldwide and poses a large socioeconomic burden, particularly in the 5% to 10% of severe asthmatics. So far, each entry of new biologics in clinical trials has led to high expectations for treating all severe asthma forms, but the outcome has only been successful if the biologic, as add-on treatment, targeted specific patient subgroups. Indeed, we now realize that asthma is a heterogeneous disease with multiple phenotypes, based on distinct pathophysiological mechanisms, called endotypes...
October 16, 2017: MAbs
https://www.readbyqxmd.com/read/29020515/manufacturing-history-of-etanercept-enbrel-%C3%A0-consistency-of-product-quality-through-major-process-revisions
#17
Brian Hassett, Ena Singh, Ehab Mahgoub, Julie O'Brien, Steven M Vicik, Brian Fitzpatrick
Etanercept (ETN) (Enbrel®) is a soluble protein that binds to, and specifically inhibits, tumor necrosis factor (TNF), a proinflammatory cytokine. ETN is synthesized in Chinese hamster ovary cells by recombinant DNA technology as a fusion protein, with a fully human TNFRII ectodomain linked to the Fc portion of human IgG1. Successful manufacture of biologics, such as ETN, requires sophisticated process and product understanding, as well as meticulous control of operations to maintain product consistency. The objective of this evaluation was to show that the product profile of ETN drug substance (DS) has been consistent over the course of production...
October 11, 2017: MAbs
https://www.readbyqxmd.com/read/29020508/variability-of-intended-copies-for-etanercept-enbrel%C3%A2-data-on-multiple-batches-of-seven-products
#18
Brian Hassett, Morton Scheinberg, Gilberto Castañeda-Hernández, Mengtao Li, Uppuluri R K Rao, Ena Singh, Ehab Mahgoub, Javier Coindreau, Julie O'Brien, Steven M Vicik, Brian Fitzpatrick
Fusion protein and monoclonal antibody-based tumor necrosis factor (TNF) inhibitors represent established treatment options for a range of inflammatory diseases. Regulatory authorities have outlined the structural characterization and clinical assessments necessary to establish biosimilarity of a new biotherapeutic product with the innovator biologic drug. Biologic products that would not meet the minimum World Health Organization's standard for evaluation of similar biotherapeutic products are available in some countries; in some cases relevant data to assess biosimilarity and appropriate regulatory approval pathways are lacking...
October 11, 2017: MAbs
https://www.readbyqxmd.com/read/28991509/safety-testing-of-monoclonal-antibodies-in-non-human-primates-case-studies-highlighting-their-impact-on-human-risk-assessment
#19
Frank R Brennan, Joy Cavagnaro, Kathleen McKeever, Patricia C Ryan, Melissa M Schutten, John Vahle, Gerhard F Weinbauer, Estelle Marrer-Berger, Lauren E Black
Monoclonal antibodies (mAbs) are improving the quality of life for patients suffering from serious diseases due to their high specificity for their target and low potential for off-target toxicity. The toxicity of mAbs is primarily driven by their pharmacological activity, and therefore safety testing of these drugs prior to clinical testing is performed in species in which the mAb binds and engages the target to a similar extent to that anticipated in humans. For highly human-specific mAbs, this testing often requires the use of non-human primates (NHPs) as relevant species...
October 9, 2017: MAbs
https://www.readbyqxmd.com/read/28991504/changes-in-complementarity-determining-regions-significantly-alter-igg-binding-to-the-neonatal-fc-receptor-fcrn-and-pharmacokinetics
#20
Nicole M Piche-Nicholas, Lindsay B Avery, Amy C King, Mania Kavosi, Mengmeng Wang, Denise M O'Hara, Lioudmila Tchistiakova, Madan Katragadda
A large body of data exists demonstrating that neonatal Fc receptor (FcRn) binding of an IgG via its Fc CH2-CH3 interface trends with the pharmacokinetics (PK) of IgG. We have observed that PK of IgG molecules vary widely, even when they share identical Fc domains. This led us to hypothesize that domains distal from the Fc could contribute to FcRn binding and affect PK. In this study, we explored the role of these IgG domains in altering the affinity between IgG and FcRn. Using a surface plasmon resonance-based assay developed to examine the steady-state binding affinity (KD) of IgG molecules to FcRn, we dissected the contributions of IgG domains in modulating the affinity between FcRn and IgG...
October 9, 2017: MAbs
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