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https://www.readbyqxmd.com/read/30010481/comparison-of-biosimilar-ct-p10-and-innovator-rituximab-in-patients-with-rheumatoid-arthritis-a-randomized-controlled-phase-3-trial
#1
Won Park, Ljubinka Božić-Majstorović, Dragana Milakovic, Alfredo Berrocal Kasay, Elias Chalouhi El-Khouri, Fedra Irazoque-Palazuelos, Francisco Fidencio Cons Molina, Pavel Shesternya, Pedro Miranda, Francisco G Medina-Rodriguez, Piotr Wiland, Slawomir Jeka, Jose Chavez-Corrales, Olena Garmish, Thomas Linde, Dmytro Rekalov, Pawel Hrycaj, Andreas Krause, Natalia Fomina, Olena Piura, Mauricio Abello-Banfi, Chang-Hee Suh, Seung Cheol Shim, Sang Joon Lee, Sung Young Lee, Sung Hwan Kim, Dae Hyun Yoo
This multinational, randomized, double-blind trial, (ClinicalTrials.gov identifier NCT02149121) was designed to demonstrate equivalence in pharmacokinetics and efficacy between CT-P10 and innovator rituximab (RTX) in patients with rheumatoid arthritis (RA). Adults with active RA were treated with CT-P10, United States-sourced RTX (US-RTX; Rituxan®), or European Union-sourced RTX (EU-RTX; MabThera®) at weeks 0 and 2. The co-primary pharmacokinetic endpoints were area under the serum concentration-time curve (AUC) from time zero to last measurable concentration (AUC0-last ), AUC from time zero to infinity (AUC0-∞ ), and maximum concentration (Cmax ) after two infusions...
July 16, 2018: MAbs
https://www.readbyqxmd.com/read/29995563/massive-parallel-screening-of-phage-libraries-for-the-generation-of-repertoires-of-human-immunomodulatory-monoclonal-antibodies
#2
Emanuele Sasso, Chiara D'Avino, Margherita Passariello, Anna Morena D'Alise, Daniela Siciliano, Maria Luisa Esposito, Guendalina Froechlich, Riccardo Cortese, Elisa Scarselli, Nicola Zambrano, Alfredo Nicosia, Claudia De Lorenzo
Immune checkpoints are emerging as novel targets for cancer therapy, and antibodies against them have shown remarkable clinical efficacy with potential for combination treatments to achieve high therapeutic index. This work aims at providing a novel approach for the generation of several novel human immunomodulatory antibodies capable of binding their targets in their native conformation and useful for therapeutic applications. We performed a massive parallel screening of phage libraries by using for the first time activated human lymphocytes to generate large collections of single-chain variable fragments (scFvs) against 10 different immune checkpoints: LAG-3, PD-L1, PD-1, TIM3, BTLA, TIGIT, OX40, 4-1BB, CD27 and ICOS...
July 11, 2018: MAbs
https://www.readbyqxmd.com/read/29993310/design-selection-and-optimization-of-an-anti-trail-r2-anti-cd3-bispecific-antibody-able-to-educate-t-cells-to-recognize-and-destroy-cancer-cells
#3
Alessandro Satta, Delia Mezzanzanica, Francesco Caroli, Barbara Frigerio, Massimo Di Nicola, Roland E Kontermann, Federico Iacovelli, Alessandro Desideri, Andrea Anichini, Silvana Canevari, Alessandro Massimo Gianni, Mariangela Figini
Recombinant human tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) or TRAIL-receptor agonistic monoclonal antibodies promote apoptosis in most cancer cells, and the differential expression of TRAIL-R2 between tumor and normal tissues allows its exploitation as a tumor-associated antigen. The use of these antibodies as anticancer agents has been extensively studied, but the results of clinical trials were disappointing. The observed lack of anticancer activity could be attributed to intrinsic or acquired resistance of tumor cells to this type of treatment...
July 11, 2018: MAbs
https://www.readbyqxmd.com/read/29985776/development-of-a-target-cell-biologics-effector-cell-tbe-complex-based-cell-killing-model-to-characterize-target-cell-depletion-by-t-cell-redirecting-bispecific-agents
#4
Xiling Jiang, Xi Chen, Thomas J Carpenter, Jun Wang, Rebecca Zhou, Hugh M Davis, Donald L Heald, Weirong Wang
T-cell redirecting bispecific antibodies (bsAbs) or antibody-derived agents that combine tumor antigen recognition with CD3-mediated T cell recruitment are highly potent tumor-killing molecules. Despite the tremendous progress achieved in the last decade, development of such bsAbs still faces many challenges. This work aimed to develop a mechanism-based pharmacokinetic/pharmacodynamic (PK/PD) modeling framework that can be used to assist the development of T-cell redirecting bsAbs. A Target cell-Biologics-Effector cell (TBE) complex-based cell killing model was developed using in vitro and in vivo data, which incorporates information on binding affinities of bsAbs to CD3 and target receptors, expression levels of CD3 and target receptors, concentrations of effector and target cells, as well as respective physiological parameters...
July 9, 2018: MAbs
https://www.readbyqxmd.com/read/29985753/comprehensive-study-of-domain-rearrangements-of-single-chain-bispecific-antibodies-to-determine-the-best-combination-of-configurations-and-microbial-host-cells
#5
Ryutaro Asano, Yuri Kuroki, Sachiko Honma, Mihoko Akabane, Shunsuke Watanabe, Shinzo Mayuzumi, Shuichi Hiyamuta, Izumi Kumagai, Koji Sode
Small bispecific antibodies (bsAbs) are important therapeutic molecules and represent the first bsAb format approved by the United States Food and Drug Administration. Diabody (Db), a small bsAb format, has four possible domain orders; we previously reported the differences in the expression levels and cancer growth inhibition effects upon rearranging the domain order of this format. However, there have been no comprehensive reports on domain rearrangements of bispecific single-chain Db (scDb) and tandem single-chain Fv (taFv), which are widely used bsAb formats...
July 9, 2018: MAbs
https://www.readbyqxmd.com/read/29969365/the-mechanism-of-gm-csf-inhibition-by-human-gm-csf-auto-antibodies-suggests-novel-therapeutic-opportunities
#6
Urmi Dhagat, Timothy R Hercus, Sophie E Broughton, Tracy L Nero, Karen S Cheung Tung Shing, Emma F Barry, Christy A Thomson, Steve Bryson, Emil F Pai, Barbara J McClure, John W Schrader, Angel F Lopez, Michael W Parker
Granulocyte-macrophage colony-stimulating factor (GM-CSF) is a hematopoietic growth factor that can stimulate a variety of cells, but its overexpression leads to excessive production and activation of granulocytes and macrophages with many pathogenic effects. This cytokine is a therapeutic target in inflammatory diseases, and several anti-GM-CSF antibodies have advanced to Phase 2 clinical trials in patients with such diseases, e.g., rheumatoid arthritis. GM-CSF is also an essential factor in preventing pulmonary alveolar proteinosis (PAP), a disease associated with GM-CSF malfunction arising most typically through the presence of GM-CSF neutralizing auto-antibodies...
July 3, 2018: MAbs
https://www.readbyqxmd.com/read/29969360/effects-of-the-fcrn-developmental-pharmacology-on-the-pharmacokinetics-of-therapeutic-monoclonal-igg-antibody-in-pediatric-subjects-using-minimal-physiologically-based-pharmacokinetic-modelling
#7
Deni Hardiansyah, Chee Meng Ng
The aim of this study was to investigate neonatal Fc receptor (FcRn) concentration developmental pharmacology in adult and pediatric subjects using minimal physiologically-based pharmacokinetic (mPBPK) modelling. Three types of pharmacokinetic (PK) data for three agents (endogenous/exogenous native IgG, bevacizumab and palivizumab) were used. The adult group contained six subjects with weights from 50 to 100 kg. For pediatric subjects, seven age groups were assumed, with five subjects each having the weight of 95%, 75%, 50%, 25% and 5% percentile of the population...
July 3, 2018: MAbs
https://www.readbyqxmd.com/read/29958069/structure-based-prediction-of-asparagine-deamidation-propensity-in-monoclonal-antibodies
#8
Qingrong Yan, Maggie Huang, Michael J Lewis, Ping Hu
Identification of asparagine (Asn) sites that are prone to deamidation is critical for the development of therapeutic monoclonal antibodies (mAbs). Despite a common chemical degradation pathway, the rates of Asn deamidation can vary dramatically among different sites, and prediction of the sensitive deamidation sites is still challenging. In this study, characterization of Asn deamidation for five IgG1 and five IgG4 mAbs under both normal and stressed conditions revealed dramatic differences in the Asn deamidation rates...
June 29, 2018: MAbs
https://www.readbyqxmd.com/read/29958062/heterologous-recombinant-expression-of-non-originator-nistmab
#9
Lila Kashi, Katharina Yandrofski, Renae J Preston, Luke W Arbogast, John P Giddens, John P Marino, John E Schiel, Zvi Kelman
The successful development and regulatory approval of originator and biosimilar therapeutic proteins requires a systems approach to upstream and downstream processing as well as product characterization and quality control. Innovation in process design and control, product characterization strategies, and data integration represent an ecosystem whose concerted advancement may reduce time-to-market and further improve comparability and biosimilarity programs. The biopharmaceutical community has made great strides to this end, yet there currently exists no pre-competitive monoclonal antibody (mAb) expression platform for open innovation...
June 29, 2018: MAbs
https://www.readbyqxmd.com/read/29958059/characterization-of-in-vivo-biotransformations-for-trastuzumab-emtansine-by-high-resolution-accurate-mass-mass-spectrometry
#10
Jintang He, Shang-Fan Yu, Sharon Yee, Surinder Kaur, Keyang Xu
Trastuzumab emtansine (T-DM1) is an antibody-drug conjugate (ADC) designed for the treatment of HER2-positive cancers. T-DM1 is composed of the humanized monoclonal antibody trastuzumab connected to a maytansine derivative cytotoxic drug, via a nonreducible thioether linker at random lysine residues, and therefore has a very complex molecular structure. It was anticipated that T-DM1 undergoes biotransformations in circulation. However, there was limited knowledge on these structural changes due to bioanalytical challenges...
June 29, 2018: MAbs
https://www.readbyqxmd.com/read/29953319/fc%C3%A4-riiia-dependent-ifn-%C3%A4-release-in-whole-blood-assay-is-predictive-of-therapeutic-igg1-antibodies-safety
#11
Nada S Alakhras, Jiabin Qiu, Guilherme V Rocha, Derrick R Witcher, Anja Koester, Jinsam You, David A Schaer, Rikke B Holmgaard, Kyla Driscoll, Jeffrey A Willy, Laurent P Malherbe
Immunomodulatory monoclonal IgG1 antibodies developed for cancer and autoimmune disease have an inherent risk of systemic release of pro-inflammatory cytokines. In vitro cytokine release assays are currently used to predict cytokine release syndrome (CRS) risk, but the validation of these preclinical tools suffers from the limited number of characterized CRS-inducing IgG1 antibodies and the poor understanding of the mechanisms regulating cytokine release. Here, we incubated human whole blood from naïve healthy volunteers with four monoclonal IgG1 antibodies with different proven or predicted capacity to elicit CRS in clinic and measured cytokine release using a multiplex assay...
June 28, 2018: MAbs
https://www.readbyqxmd.com/read/29947573/extending-human-igg-half-life-using-structure-guided-design
#12
Brian J Booth, Boopathy Ramakrishnan, Kristin Narayan, Andrew M Wollacott, Gregory J Babcock, Zachary Shriver, Karthik Viswanathan
Engineering of antibodies for improved pharmacokinetics through enhanced binding to the neonatal Fc receptor (FcRn) has been demonstrated in transgenic mice, non-human primates and humans. Traditionally, such approaches have largely relied on random mutagenesis and display formats, which fail to address related critical attributes of the antibody, such as effector functions or biophysical stability. We have developed a structure- and network-based framework to interrogate the engagement of IgG with multiple Fc receptors (FcRn, C1q, TRIM21, FcγRI, FcγRIIa/b, FcγRIIIa) simultaneously...
June 27, 2018: MAbs
https://www.readbyqxmd.com/read/29944439/antibody-pharmacokinetics-in-rat-brain-determined-using-microdialysis
#13
Hsueh-Yuan Chang, Kasey Morrow, Emily Bonacquisti, WanYing Zhang, Dhaval K Shah
Here, we present the first case-study where microdialysis is used to investigate the pharmacokinetics of antibody in different regions of rat brain. Endogenous IgG was used to understand antibody disposition at steady-state and exogenously administered trastuzumab was used to understand the disposition in a dynamic setting. Microdialysis samples from the striatum (ST), lateral ventricle (LV), and cisterna magna (CM) were collected, along with plasma and brain homogenate, to comprehensively understand brain pharmacokinetics of antibodies...
June 26, 2018: MAbs
https://www.readbyqxmd.com/read/29916758/antigen-recognition-by-single-domain-antibodies-structural-latitudes-and-constraints
#14
Kevin A Henry, C Roger MacKenzie
Single-domain antibodies (sdAbs), the autonomous variable domains of heavy chain-only antibodies produced naturally by camelid ungulates and cartilaginous fishes, have evolved to bind antigen using only three complementarity-determining region (CDR) loops rather than the six present in conventional VH :VL antibodies. It has been suggested, based on limited evidence, that sdAbs may adopt paratope structures that predispose them to preferential recognition of recessed protein epitopes, but poor or non-recognition of protuberant epitopes and small molecules...
June 19, 2018: MAbs
https://www.readbyqxmd.com/read/29913099/corrigendum
#15
(no author information available yet)
No abstract text is available yet for this article.
June 18, 2018: MAbs
https://www.readbyqxmd.com/read/29771629/brain-uptake-of-multivalent-and-multi-specific-dvd-ig-proteins-after-systemic-administration
#16
Denise Karaoglu Hanzatian, Annette Schwartz, Farid Gizatullin, Jamie Erickson, Kangwen Deng, Ruth Villanueva, Christopher Stedman, Cristina Harris, Tariq Ghayur, Andrew Goodearl
Therapeutic monoclonal antibodies and endogenous IgG antibodies show limited uptake into the central nervous system (CNS) due to the blood-brain barrier (BBB), which regulates and controls the selective and specific transport of both exogenous and endogenous materials to the brain. The use of natural transport mechanisms, such as receptor-mediated transcytosis (RMT), to deliver antibody therapeutics into the brain have been studied in rodents and monkeys. Recent successful examples include monovalent bispecific antibodies and mono- or bivalent fusion proteins; however, these formats do not have the capability to bind to both the CNS target and the BBB transport receptor in a bivalent fashion as a canonical antibody would...
May 17, 2018: MAbs
https://www.readbyqxmd.com/read/29757698/prediction-of-non-linear-pharmacokinetics-in-humans-of-an-antibody-drug-conjugate-adc-when-evaluation-of-higher-doses-in-animals-is-limited-by-tolerability-case-study-with-an-anti-cd33-adc
#17
Isabel Figueroa, Doug Leipold, Steve Leong, Bing Zheng, Montserrat Triguero-Carrasco, Aimee Fourie-O'Donohue, Katherine R Kozak, Keyang Xu, Melissa Schutten, Hong Wang, Andrew G Polson, Amrita V Kamath
For antibody-drug conjugates (ADCs) that carry a cytotoxic drug, doses that can be administered in preclinical studies are typically limited by tolerability, leading to a narrow dose range that can be tested. For molecules with non-linear pharmacokinetics (PK), this limited dose range may be insufficient to fully characterize the PK of the ADC and limits translation to humans. Mathematical PK models are frequently used for molecule selection during preclinical drug development and for translational predictions to guide clinical study design...
May 14, 2018: MAbs
https://www.readbyqxmd.com/read/29733750/delivery-of-alx-0171-by-inhalation-greatly-reduces-respiratory-syncytial-virus-disease-in-newborn-lambs
#18
Alejandro Larios Mora, Laurent Detalle, Jack M Gallup, Albert Van Geelen, Thomas Stohr, Linde Duprez, Mark R Ackermann
Respiratory syncytial virus (RSV) is a common cause of acute lower respiratory disease in infants and young children worldwide. Currently, treatment is supportive and no vaccines are available. The use of newborn lambs to model hRSV infection in human infants may provide a valuable tool to assess safety and efficacy of new antiviral drugs and vaccines. ALX-0171 is a trivalent Nanobody targeting the hRSV fusion (F) protein and its therapeutic potential was evaluated in newborn lambs infected with a human strain of RSV followed by daily ALX-0171 nebulization for 3 or 5 consecutive days...
May 7, 2018: MAbs
https://www.readbyqxmd.com/read/29733746/the-less-is-more-in-therapeutic-antibodies-afucosylated-anti-cancer-antibodies-with-enhanced-antibody-dependent-cellular-cytotoxicity
#19
Natasha A Pereira, Kah Fai Chan, Pao Chun Lin, Zhiwei Song
Therapeutic monoclonal antibodies are the fastest growing class of biological therapeutics for the treatment of various cancers and inflammatory disorders. In cancer immunotherapy, some IgG1 antibodies rely on the Fc-mediated immune effector function, antibody-dependent cellular cytotoxicity (ADCC), as the major mode of action to deplete tumor cells. It is well-known that this effector function is modulated by the N-linked glycosylation in the Fc region of the antibody. In particular, absence of core fucose on the Fc N-glycan has been shown to increase IgG1 Fc binding affinity to the FcγRIIIa present on immune effector cells such as natural killer cells and lead to enhanced ADCC activity...
May 7, 2018: MAbs
https://www.readbyqxmd.com/read/29708852/fab-is-the-most-efficient-format-to-express-functional-antibodies-by-yeast-surface-display
#20
Coline Sivelle, Raphaël Sierocki, Kelly Ferreira-Pinto, Stéphanie Simon, Bernard Maillere, Hervé Nozach
Multiple formats are available for engineering of monoclonal antibodies (mAbs) by yeast surface display, but they do not all lead to efficient expression of functional molecules. We therefore expressed four anti-tumor necrosis factor and two anti-IpaD mAbs as single-chain variable fragment (scFv), antigen-binding fragment (Fab) or single-chain Fabs and compared their expression levels and antigen-binding efficiency. Although the scFv and scFab formats are widely used in the literature, 2 of 6 antibodies were either not or weakly expressed...
April 30, 2018: MAbs
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