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https://www.readbyqxmd.com/read/29035675/practical-considerations-in-clinical-strategy-to-support-the-development-of-injectable-drug-device-combination-products-for-biologics
#1
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/29035637/design-and-characterization-of-mp0250-a-tri-specific-anti-hgf-anti-vegf-darpin%C3%A2-drug-candidate
#2
H Kaspar Binz, Talitha R Bakker, Douglas J Phillips, Andreas Cornelius, Christof Zitt, Thomas Göttler, Gabriel Sigrist, Ulrike Fiedler, Savira Ekawardhani, Ignacio Dolado, Johan Abram Saliba, Gaby Tresch, Karl Proba, Michael T Stumpp
MP0250 is a multi-domain drug candidate currently being tested in clinical trials for the treatment of cancer. It comprises one anti-vascular endothelial growth factor-A (VEGF-A), one anti-hepatocyte growth factor (HGF), and two anti-human serum albumin (HSA) DARPin® domains within a single polypeptide chain. While there is first clinical validation of a single-domain DARPin® drug candidate, little is known about DARPin® drug candidates comprising multiple domains. Here, we show that MP0250 can be expressed at 15 g/L in soluble form in E...
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
#3
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
#4
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
#5
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
#6
Brian Hassett, Morton Scheinberg, Gilberto Castañeda-Hernández, Mengtao Li, Uppuluri Rk 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
#7
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
#8
Nicole M Piche-Nicholas, Amy C King, Lindsay B Avery, 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
https://www.readbyqxmd.com/read/28985159/international-standards-for-monoclonal-antibodies-to-support-pre-and-post-marketing-product-consistency-evaluation-of-a-candidate-international-standard-for-the-bioactivities-of-rituximab
#9
Sandra Prior, Simon E Hufton, Bernard Fox, Thomas Dougall, Peter Rigsby, Adrian Bristow
The intrinsic complexity and heterogeneity of therapeutic monoclonal antibodies is built into the biosimilarity paradigm where critical quality attributes are controlled in exhaustive comparability studies with the reference medicinal product. The long-term success of biosimilars will depend on reassuring healthcare professionals and patients of consistent product quality, safety and efficacy. With this aim, the World Health Organization has endorsed the need for public bioactivity standards for therapeutic monoclonal antibodies in support of current controls...
October 6, 2017: MAbs
https://www.readbyqxmd.com/read/28952876/structure-and-characterization-of-a-high-affinity-c5a-monoclonal-antibody-that-blocks-binding-to-c5ar1-and-c5ar2-receptors
#10
Caroline S Colley, Bojana Popovic, Sudharsan Sridharan, Judit E Debreczeni, David Hargeaves, Michael Fung, An Ling-Ling, Bryan Edwards, Joanne Arnold, Elizabeth England, Laura Eghobamien, Ulf Sivars, Liz Flavell, Jonathan Renshaw, Kate Wickson, Paul Warrener, Jingying Zha, Jessica Bonnell, Rob Woods, Trevor Wilkinson, Claire Dobson, Tristan J Vaughan
C5a is a potent anaphylatoxin that modulates inflammation through the C5aR1 and C5aR2 receptors. The molecular interactions between C5a-C5aR1 receptor are well defined, whereas C5a-C5aR2 receptor interactions are poorly understood. Here, we describe the generation of a human antibody, MEDI7814, that neutralizes C5a and C5adesArg binding to the C5aR1 and C5aR2 receptors, without affecting complement-mediated bacterial cell killing. Unlike other anti-C5a mAbs described, this antibody has been shown to inhibit the effects of C5a by blocking C5a binding to both C5aR1 and C5aR2 receptors...
September 27, 2017: MAbs
https://www.readbyqxmd.com/read/28933661/suppressing-allostery-in-epitope-mapping-experiments-using-millisecond-hydrogen-deuterium-exchange-mass-spectrometry
#11
Bin Deng, Shaolong Zhu, Andrew M Macklin, Jianrong Xu, Cristina Lento, Adnan Sljoka, Derek J Wilson
Localization of the interface between the candidate antibody and its antigen target, commonly known as epitope mapping, is a critical component of the development of therapeutic monoclonal antibodies. With the recent availability of commercial automated systems, hydrogen / deuterium eXchange (HDX) is rapidly becoming the tool for mapping epitopes preferred by researchers in both industry and academia. However, this approach has a significant drawback in that it can be confounded by 'allosteric' structural and dynamic changes that result from the interaction, but occur far from the point(s) of contact...
September 21, 2017: MAbs
https://www.readbyqxmd.com/read/28933642/epitope-characterization-of-anti-jam-a-antibodies-using-orthogonal-mass-spectrometry-and-surface-plasmon-resonance-approaches
#12
Guillaume Terral, Thierry Champion, François Debaene, Olivier Colas, Maxime Bourguet, Elsa Wagner-Rousset, Nathalie Corvaia, Alain Beck, Sarah Cianferani
Junctional adhesion molecule-A (JAM-A) is an adherens and tight junction protein expressed by endothelial and epithelial cells and associated with cancer progression. We present here the extensive characterization of immune complexes involving JAM-A antigen and three monoclonal antibodies (mAbs), including hz6F4-2, a humanized version of anti-tumoral 6F4 mAb identified by a functional and proteomic approach in our laboratory. A specific workflow that combines orthogonal approaches has been designed to determine binding stoichiometries along with JAM-A epitope mapping determination at high resolution for these three mAbs...
September 21, 2017: MAbs
https://www.readbyqxmd.com/read/28933630/going-native-direct-high-throughput-screening-of-secreted-full-length-igg-antibodies-against-cell-membrane-proteins
#13
Yongliang Fang, Thach H Chu, Margaret E Ackerman, Karl E Griswold
Gel microdroplet - fluorescence activated cell sorting (GMD-FACS) is an innovative high throughput screening platform for recombinant protein libraries, and we show here that GMD-FACS can overcome many of the limitations associated with conventional screening methods for antibody libraries. For example, phage and cell surface display benefit from exceptionally high throughput, but generally require high quality, soluble antigen target and necessitate the use of anchored antibody fragments. In contrast, the GMD-FACS assay can screen for soluble, secreted, full-length IgGs at rates of several thousand clones per second, and the technique enables direct screening against membrane protein targets in their native cellular context...
September 21, 2017: MAbs
https://www.readbyqxmd.com/read/28898162/modulation-of-protein-a-binding-allows-single-step-purification-of-mouse-bispecific-antibodies-that-retain-fcrn-binding
#14
Adam Zwolak, Anthony A Armstrong, Susan H Tam, Jose R Pardinas, Dennis R Goulet, Songmao Zheng, Kerry Brosnan, Eva Emmell, Jeffrey Luo, Gary L Gilliland, Mark L Chiu
The increased number of bispecific antibodies (BsAb) under therapeutic development has resulted in a need for mouse surrogate BsAbs. Here, we describe a one-step method for generating highly pure mouse BsAbs suitable for in vitro and in vivo studies. We identify two mutations in the mouse IgG2a and IgG2b Fc region: one that eliminates protein A binding and one that enhances protein A binding by 8-fold. We show that BsAbs harboring these mutations can be purified from the residual parental monoclonal antibodies in one step using protein A affinity chromatography...
September 12, 2017: MAbs
https://www.readbyqxmd.com/read/28895795/glycan-characterization-of-the-nist-rm-monoclonal-antibody-using-a-total-analytical-solution-from-sample-preparation-to-data-analysis
#15
Mark Hilliard, William R Alley, Ciara A McManus, Ying Qing Yu, Sinead Hallinan, John Gebler, Pauline M Rudd
Glycosylation is an important attribute of biopharmaceutical products to monitor from development through production. However, glycosylation analysis has traditionally been a time-consuming process with long sample preparation protocols and manual interpretation of the data. To address the challenges associated with glycan analysis, we developed a streamlined analytical solution that covers the entire process from sample preparation to data analysis. In this communication, we describe the complete analytical solution that begins with a simplified and fast N-linked glycan sample preparation protocol that can be completed in less than 1 hr...
September 12, 2017: MAbs
https://www.readbyqxmd.com/read/28895785/preclinical-pharmacokinetic-characterization-of-an-adipose-tissue-targeting-monoclonal-antibody-in-obese-and-non-obese-animals
#16
Sharmila Rajan, Danielle Mandikian, Amos Baruch, Thomas R Gelzleichter, Dale Stevens, Junichiro Sonoda, Kyra Cowan, C Andrew Boswell, Eric Stefanich
Target receptor levels can influence pharmacokinetics (PK) or pharmacodynamics (PD) of monoclonal antibodies (mAbs), and can affect drug development of this class of molecules. We generated an effector-less humanized bispecific antibody that selectively activates fibroblast growth factor receptor (FGFR)1 and βKlotho receptor, a FGF21 receptor complex highly expressed in both white and brown adipocytes. The molecule shows cross-species binding with comparable equilibrium binding affinity (Kd) for human, cynomolgus monkey, and mouse FGFR1/βKlotho...
September 12, 2017: MAbs
https://www.readbyqxmd.com/read/28876162/capacity-limits-of-asialoglycoprotein-receptor-mediated-liver-targeting
#17
Charlotte Bon, Thomas Hofer, Alain Bousquet-Mélou, Mark R Davies, Ben-Fillippo Krippendorff
The abundant cell surface asialoglycoprotein receptor (ASGPR) is a highly selective receptor found on hepatocytes that potentially can be exploited as a selective shuttle for delivery. Various nucleic acid therapeutics that bind ASGPR are already in clinical development, but this receptor-mediated delivery mechanism can be saturated, which will likely result in reduced selectivity for the liver and therefore increase the likelihood for systemic adverse effects. Therefore, when aiming to utilize this mechanism, it is important to optimize both the administration protocol and the molecular properties...
September 6, 2017: MAbs
https://www.readbyqxmd.com/read/28873009/-89-zr-mab3481-pet-for-her3-tumor-status-assessment-during-lapatinib-treatment
#18
Martin Pool, Arjan Kol, Steven de Jong, Elisabeth G E de Vries, Marjolijn N Lub-de Hooge, Anton G T Terwisscha van Scheltinga
Treatment of human epidermal growth factor receptor 2 (HER2)-driven breast cancer with tyrosine kinase inhibitor lapatinib can induce a compensatory HER3 increase, which may attenuate antitumor efficacy. Therefore, we explored in vivo HER3 tumor status assessment after lapatinib treatment with zirconium-89 ((89)Zr)-labeled anti-HER3 antibody mAb3481 positron emission tomography (PET). Lapatinib effects on HER3 cell surface expression and mAb3481 internalization were evaluated in human breast (BT474, SKBR3) and gastric (N87) cancer cell lines using flow cytometry...
September 5, 2017: MAbs
https://www.readbyqxmd.com/read/28854082/protein-engineering-to-increase-the-potential-of-a-therapeutic-antibody-fab-for-long-acting-delivery-to-the-eye
#19
Devin Tesar, Jacob Luoma, Emily A Wyatt, Catherine Shi, Whitney Shatz, Philip E Hass, Mary Mathieu, Li Yi, Jacob E Corn, Katie F Maass, Kathryn Wang, Michelle Z Dion, Nisana Andersen, Kelly M Loyet, Menno van Lookeren Campagne, Karthikan Rajagopal, Leslie Dickmann, Justin M Scheer, Robert F Kelley
To date, ocular antibody therapies for the treatment of retinal diseases rely on injection of the drug into the vitreous chamber of the eye. Given the burden for patients undergoing this procedure, less frequent dosing through the use of long-acting delivery (LAD) technologies is highly desirable. These technologies usually require a highly concentrated formulation and the antibody must be stable against extended exposure to physiological conditions. Here we have increased the potential of a therapeutic antibody antigen-binding fragment (Fab) for LAD by using protein engineering to enhance the chemical and physical stability of the molecule...
August 30, 2017: MAbs
https://www.readbyqxmd.com/read/28853987/forced-degradation-of-recombinant-monoclonal-antibodies-a-practical-guide
#20
Christine Nowak, Jason Cheung, Shara Dellatore, Amit Katiyar, Ram Bhat, Joanne Sun, Gomathinayagam Ponniah, Alyssa Neill, Bruce Mason, Alain Beck, Hongcheng Liu
Forced degradation studies have become integral to the development of recombinant monoclonal antibody therapeutics by serving a variety of objectives from early stage manufacturability evaluation to supporting comparability assessments both pre- and post- marketing approval. This review summarizes the regulatory guidance scattered throughout different documents to highlight the expectations from various agencies such as the Food and Drug Administration and European Medicines Agency. The various purposes for forced degradation studies, commonly used conditions and the major degradation pathways under each condition are also discussed...
August 30, 2017: MAbs
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