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dual variable domain immunoglobulin

Kun Ding, Lucia Eaton, Diana Bowley, Matthew Rieser, Qing Chang, Maria C Harris, Anca Clabbers, Feng Dong, Jikui Shen, Sean F Hackett, Debra S Touw, Jacqueline Bixby, Suju Zhong, Lorenzo Benatuil, Sahana Bose, Christine Grinnell, Gregory M Preston, Ramesh Iyer, Ramkrishna Sadhukhan, Susan Marchie, Gary Overmeyer, Tariq Ghayur, Deborah A van Riet, Shibo Tang, Peter A Campochario, Jijie Gu
Exudative age-related macular degeneration (AMD) is the most common cause of moderate and severe vision loss in developed countries. Intraocular injections of vascular endothelial growth factor (VEGF or VEGF-A)-neutralizing proteins provide substantial benefit, but frequent, long-term injections are needed. In addition, many patients experience initial visual gains that are ultimately lost due to subretinal fibrosis. Preclinical studies and early phase clinical trials suggest that combined suppression of VEGF and platelet-derived growth factor-BB (PDGF-BB) provides better outcomes than suppression of VEGF alone, due to more frequent regression of neovascularization (NV) and suppression of subretinal fibrosis...
February 2017: MAbs
Pragya Yadav, Matthew T Carr, Ruby Yu, Alice Mumbey-Wafula, Linda A Spatz
INTRODUCTION: The Epstein Barr Virus (EBV) has been associated with the autoimmune disease, Systemic Lupus Erythematosus (SLE). EBV nuclear antigen-I (EBNA-1) is the major nuclear protein of EBV. We previously generated an IgG monoclonal antibody (MAb) to EBNA-1, 3D4, and demonstrated that it cross-reacts with double stranded DNA (dsDNA) and binds the 148 amino acid viral binding site (VBS) in the carboxyl region of EBNA-1. The aim of the present study was to characterize another antibody to EBNA-1 that cross-reacts with dsDNA, compare its immunoglobulin genes to 3D4, and finely map the epitope in EBNA-1 that is recognized by these cross-reactive antibodies...
September 2016: Immunity, Inflammation and Disease
Matthew P Kosloski, Sandra Goss, Susanne X Wang, Jia Liu, Ralf Loebbert, Jeroen K Medema, Wei Liu, Sandeep Dutta
The interleukin (IL)-1 family of proinflammatory cytokines are thought to play a significant role in the structural progression of osteoarthritis and its associated symptoms. IL-1α and IL-1β are 2 distinct cytokines found in the cartilage, synovial membrane, and synovial fluid of patients with osteoarthritis. The aim of these studies was to evaluate the pharmacokinetics of ABT-981, a dual variable domain immunoglobulin (DVD-Ig) capable of simultaneously binding IL-1α and IL-1β, in healthy subjects and patients with osteoarthritis of the knee...
December 2016: Journal of Clinical Pharmacology
Anke Steinmetz, François Vallée, Christian Beil, Christian Lange, Nicolas Baurin, Jochen Beninga, Cécile Capdevila, Carsten Corvey, Alain Dupuy, Paul Ferrari, Alexey Rak, Peter Wonerow, Jochen Kruip, Vincent Mikol, Ercole Rao
Bispecific immunoglobulins (Igs) typically contain at least two distinct variable domains (Fv) that bind to two different target proteins. They are conceived to facilitate clinical development of biotherapeutic agents for diseases where improved clinical outcome is obtained or expected by combination therapy compared to treatment by single agents. Almost all existing formats are linear in their concept and differ widely in drug-like and manufacture-related properties. To overcome their major limitations, we designed cross-over dual variable Ig-like proteins (CODV-Ig)...
July 2016: MAbs
Ashlesha S Raut, Devendra S Kalonia
Liquid-liquid phase separation (LLPS) and aggregation can reduce the physical stability of therapeutic protein formulations. On undergoing LLPS, the protein-rich phase can promote aggregation during storage due to high concentration of the protein. Effect of different excipients on aggregation in protein solution is well documented; however data on the effect of excipients on LLPS is scarce in the literature. In this study, the effect of four excipients (PEG 400, Tween 80, sucrose, and hydroxypropyl beta-cyclodextrin (HPβCD)) on liquid-liquid phase separation and aggregation in a dual variable domain immunoglobulin protein solution was investigated...
March 7, 2016: Molecular Pharmaceutics
Ashlesha S Raut, Devendra S Kalonia
PURPOSE: Increased solution viscosity results in difficulties in manufacturing and delivery of therapeutic protein formulations, increasing both the time and production costs, and leading to patient inconvenience. The solution viscosity is affected by the molecular properties of both the solute and the solvent. The purpose of this work was to investigate the effect of size, charge and protein-protein interactions on the viscosity of Dual Variable Domain Immunoglobulin (DVD-Ig(TM)) protein solutions...
January 2016: Pharmaceutical Research
Ashlesha S Raut, Devendra S Kalonia
Dual variable domain immunoglobulin proteins (DVD-Ig proteins) are large molecules (MW ∼ 200 kDa) with increased asymmetry because of their extended Y-like shape, which results in increased formulation challenges. Liquid-liquid phase separation (LLPS) of protein solutions into protein-rich and protein-poor phases reduces solution stability at intermediate concentrations and lower temperatures, and is a serious concern in formulation development as therapeutic proteins are generally stored at refrigerated conditions...
September 8, 2015: Molecular Pharmaceutics
Jinming Gu, Jinsong Yang, Qing Chang, Zhihong Liu, Tariq Ghayur, Jijie Gu
Epidermal growth factor receptor (EGFR) and receptor tyrosine-protein kinase 3 (ErbB3) are two well-established targets in cancer therapy. There is significant crosstalk among these two receptors and others. To block signaling from both EGFR and ErbB3, we generated anti-EGFR and anti-ErbB3 DVD-Ig proteins. Two DVD-Ig proteins maintained the functions of the combination of the two parental antibodies. The DVD-Ig proteins inhibit cell signaling and proliferation in A431 and FaDu cells while half DVD-Ig proteins lost proliferation inhibition function...
2015: PloS One
Patrick Hossler, Min Wang, Sean McDermott, Christopher Racicot, Kofi Chemfe, Yun Zhang, Christopher Chumsae, Anton Manuilov
Charge variants in recombinant proteins are an important series of protein modifications, whose potential role on protein stability, activity, immunogenicity, and pharmacokinetics continues to be studied. Monoclonal antibodies in particular have been shown to have a wide range of acidic species variants, including those associated with the addition of covalent modifications as well as the chemical degradation at specific peptide regions on the antibody. These variants play a significant role toward the overall heterogeneity of recombinant therapeutic proteins and are typically monitored during manufacturing to ensure they lie within proven acceptable ranges...
July 2015: Biotechnology Progress
Susan E Lacy, Chengbin Wu, Dominic J Ambrosi, Chung-Ming Hsieh, Sahana Bose, Renee Miller, Donna M Conlon, Edit Tarcsa, Ravi Chari, Tariq Ghayur, Rajesh V Kamath
Interleukin-1 (IL-1) cytokines such as IL-1α, IL-1β, and IL-1Ra contribute to immune regulation and inflammatory processes by exerting a wide range of cellular responses, including expression of cytokines and chemokines, matrix metalloproteinases, and nitric oxide synthetase. IL-1α and IL-1β bind to IL-1R1 complexed to the IL-1 receptor accessory protein and induce similar physiological effects. Preclinical and clinical studies provide significant evidence for the role of IL-1 in the pathogenesis of osteoarthritis (OA), including cartilage degradation, bone sclerosis, and synovial proliferation...
2015: MAbs
Jinming Gu, Jinsong Yang, Qing Chang, Xiaoqing Lu, Jieyi Wang, Mingjiu Chen, Tariq Ghayur, Jijie Gu
Inhibiting ErbB2 signaling with monoclonal antibodies (mAbs) or small molecules is an established therapeutic strategy in oncology. We have developed anti-ErbB2 Dual Variable Domain Immunoglobulin (DVD-Ig) proteins that capture the function of a combination of two anti-ErbB2 antibodies. In addition, some of the anti-ErbB2 DVD-Ig proteins gain the new functions of enhancing ErbB2 signaling and cell proliferation in N87 cells. We further found that two DVD-Ig proteins, DVD687 and DVD688, have two distinct mechanisms of actions in Calu-3 and N87 cells...
2014: PloS One
Ivan Correia, Joyce Sung, Randall Burton, Clarissa G Jakob, Bridget Carragher, Tariq Ghayur, Czeslaw Radziejewski
A dual-specific, tetravalent immunoglobulin G-like molecule, termed dual variable domain immunoglobulin (DVD-Ig™), is engineered to block two targets. Flexibility modulates Fc receptor and complement binding, but could result in undesirable cross-linking of surface antigens and downstream signaling. Understanding the flexibility of parental mAbs is important for designing and retaining functionality of DVD-Ig™ molecules. The architecture and dynamics of a DVD-Ig™ molecule and its parental mAbs was examined using single particle electron microscopy...
May 2013: MAbs
Clarissa G Jakob, Rohinton Edalji, Russell A Judge, Enrico DiGiammarino, Yingchun Li, Jijie Gu, Tariq Ghayur
Several bispecific antibody-based formats have been developed over the past 25 years in an effort to produce a new generation of immunotherapeutics that target two or more disease mechanisms simultaneously. One such format, the dual-variable domain immunoglobulin (DVD-Ig™), combines the target binding domains of two monoclonal antibodies via flexible naturally occurring linkers, which yields a tetravalent IgG - like molecule. We report the structure of an interleukin (IL)12-IL18 DVD-Ig™ Fab (DFab) fragment with IL18 bound to the inner variable domain (VD) that reveals the remarkable flexibility of the DVD-Ig™ molecule and how the DVD-Ig™ format can function to bind four antigens simultaneously...
May 2013: MAbs
Marion T Kasaian, Kimberly Marquette, Susan Fish, Charlene DeClercq, Rita Agostinelli, Timothy A Cook, Agnes Brennan, Julie Lee, Lori Fitz, Jonathan Brooks, Yulia Vugmeyster, Cara M M Williams, Alan Lofquist, Lioudmila Tchistiakova
IL-4 and IL-13 comprise promising targets for therapeutic interventions in asthma and other Th2-associated diseases, but agents targeting either IL-4 or IL-13 alone have shown limited efficacy in human clinical studies. Because these cytokines may involve redundant function, dual targeting holds promise for achieving greater efficacy. We describe a bifunctional therapeutic targeting IL-4 and IL-13, developed by a combination of specific binding domains. IL-4-targeted and IL-13-targeted single chain variable fragments were joined in an optimal configuration, using appropriate linker regions on a novel protein scaffold...
July 2013: American Journal of Respiratory Cell and Molecular Biology
Xi Yang, Qing Zhao, Liping Zhu, Wei Zhang
The Fc alpha/mu receptor (Fcα/μR, CD351) is a receptor that has dual specificity for IgA and IgM. Its second extracellular domain (EC2) has an Ig variable region-like structure and is predicted to be the ligand binding domain. EC2 is homologous to the first Ig-like domain (D1) of polymeric Ig receptor (pIgR) and has three complementarity-determining region (CDR)-like loops. A peptide that includes the CDR1-like loop region has been found to be responsible for IgA and IgM binding. However, whether the CDR2- and CDR3-like loops of EC2 contribute to ligand binding has remained unclear...
May 2013: Immunobiology
Oliver Seifert, Aline Plappert, Nadine Heidel, Sina Fellermeier, Sylvia K E Messerschmidt, Fabian Richter, Roland E Kontermann
Dimeric assembly of antibody fragments and other therapeutic molecules can result in increased binding and improved bioactivity. Here, we investigated the use of the IgM heavy chain domain 2 (MHD2) as covalently linked homodimerization module. Fusion of single-chain fragment variable (scFv) molecules directed against epidermal growth factor receptor (EGFR) and human epidermal growth factor receptor 2 to the N- and/or C-terminus of the MHD2, respectively, resulted in molecules with single or dual specificity for tumor cells...
October 2012: Protein Engineering, Design & Selection: PEDS
Enrico DiGiammarino, Tariq Ghayur, Junjian Liu
The dual variable domain immunoglobulin (DVD-Ig™) protein is a new type of dual-specific IgG. As a novel therapeutic class, the great potential of the DVD-Ig protein is to simultaneously target two mediators of disease by a single pharmaceutical entity. The molecule contains an Fc region and constant regions in a configuration similar to a conventional IgG; however, the DVD-Ig protein is unique in that each arm of the molecule contains two variable domains (VDs). The VDs within an arm are linked in tandem and can possess different binding specificities...
2012: Methods in Molecular Biology
Jijie Gu, Tariq Ghayur
Bispecific antibodies may be used to improve clinical efficacy by targeting two disease mechanisms for the treatment of complex human diseases in a single agent. Bispecific antibodies also hold promise for certain therapeutic applications difficult to achieve by single-targeting monospecific antibodies, such as immune (T cell or NK) cell retargeting, site-specific targeting, enabling therapeutics to cross the blood-brain barrier, and unique receptor modulation. Although the history of bispecific antibody research is almost as long as hybridoma technology, it is not until recent that bispecific antibodies have made substantial breakthrough, thanks to promising clinical trial results of a few bispecific antibodies and the development of new formats which largely ease manufacturing and physicochemical property challenges encountered by early bispecific antibody formats...
2012: Methods in Enzymology
Jochen Govaert, Mireille Pellis, Nick Deschacht, Cécile Vincke, Katja Conrath, Serge Muyldermans, Dirk Saerens
The antigen-binding fragment of functional heavy chain antibodies (HCAbs) in camelids comprises a single domain, named the variable domain of heavy chain of HCAbs (VHH). The VHH harbors remarkable amino acid substitutions in the framework region-2 to generate an antigen-binding domain that functions in the absence of a light chain partner. The substitutions provide a more hydrophilic, hence more soluble, character to the VHH but decrease the intrinsic stability of the domain. Here we investigate the functional role of an additional hallmark of dromedary VHHs, i...
January 13, 2012: Journal of Biological Chemistry
Vineet Kumar, Nitin Dixit, Liqiang Lisa Zhou, Wolfgang Fraunhofer
The purpose of this work was to determine the nature of long and short-range forces governing protein aggregation kinetics at low and high concentrations for a monoclonal antibody (IgG1) and a dual-variable-domain immunoglobulin (DVD-Ig). Protein-protein interactions (PPI) were studied under dilute conditions by utilizing the methods of static (B(22)) and dynamic light scattering (k(D)). PPI in solutions containing minimal ionic strengths were characterized to get detailed insights into the impact of ionic strength on aggregation...
December 12, 2011: International Journal of Pharmaceutics
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