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dual variable domain immunoglobulin

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
Yingchun Li, Jonathan A Hickson, Dominic J Ambrosi, Deanna L Haasch, Kelly D Foster-Duke, Lucia J Eaton, Enrico L DiGiammarino, Sanjay C Panchal, Fang Jiang, Sarah R Mudd, Catherine Zhang, Surekha S Akella, Wenqing Gao, Sherry L Ralston, Louie Naumovski, Jijie Gu, Susan E Morgan-Lappe
Antiangiogenic therapy is a clinically validated modality in cancer treatment. To date, all approved antiangiogenic drugs primarily inhibit the VEGF pathway. Delta-like ligand 4 (DLL4) has been identified as a potential drug target in VEGF-independent angiogenesis and tumor-initiating cell (TIC) survival. A dual-specific biologic targeting both VEGF and DLL4 could be an attractive strategy to improve the effectiveness of anti-VEGF therapy. ABT-165 was uniquely engineered using a proprietary dual-variable domain immunoglobulin (DVD-Ig) technology based on its ability to bind and inhibit both DLL4 and VEGF...
May 2018: Molecular Cancer Therapeutics
Amit Khatri, Ahmed A Othman
ABT-122 is an IgG1 dual-variable domain immunoglobulin that specifically blocks TNF-α and IL-17A. This work characterized ABT-122 pharmacokinetics using nonlinear mixed-effects modeling and ABT-122 serum concentrations from 72 healthy subjects, 196 subjects with rheumatoid arthritis (RA), and 144 subjects with psoriatic arthritis (PsA) enrolled in 4 phase 1 and 2 phase 2 studies (0.1-10 mg/kg intravenously and 0.3-3 mg/kg subcutaneous single doses and 0.3-3.0 mg/kg subcutaneous and 60-240 mg subcutaneous doses weekly or every other week)...
January 24, 2018: Journal of Clinical Pharmacology
S X Wang, S B Abramson, M Attur, M A Karsdal, R A Preston, C J Lozada, M P Kosloski, F Hong, P Jiang, M J Saltarelli, B A Hendrickson, J K Medema
OBJECTIVE: To investigate the safety, tolerability, pharmacokinetics, and pharmacodynamics of ABT-981, a human dual variable domain immunoglobulin simultaneously targeting interleukin (IL)-1α and IL-1β, in patients with knee osteoarthritis (OA). METHOD: This was a randomized, double-blind, placebo-controlled, single-center study of multiple subcutaneous (SC) injections of ABT-981 in patients with mild-to-moderate OA of the knee (NCT01668511). Three cohorts received ABT-981 (0...
December 2017: Osteoarthritis and Cartilage
Roy M Fleischmann, Frank Wagner, Alan J Kivitz, Heikki T Mansikka, Nasser Khan, Ahmed A Othman, Amit Khatri, Feng Hong, Ping Jiang, Melanie Ruzek, Robert J Padley
OBJECTIVE: Tumor necrosis factor (TNF) and interleukin-17 (IL-17) independently contribute to the pathophysiology of rheumatoid arthritis (RA). ABT-122 is a novel dual variable domain immunoglobulin that selectively and simultaneously targets human TNF and IL-17A. The aim of treatment with ABT-122 is to evoke a greater clinical response than that achieved by targeting either cytokine alone. This study was undertaken to present the pooled safety, tolerability, and exploratory pharmacodynamics of ABT-122 based on 2 phase I, placebo-controlled, multiple ascending-dose studies in patients with primarily inactive RA...
December 2017: Arthritis & Rheumatology
Amit Khatri, Sandra Goss, Ping Jiang, Heikki Mansikka, Ahmed A Othman
BACKGROUND AND OBJECTIVE: ABT-122 is a dual-variable domain immunoglobulin that neutralizes both tumor necrosis factor-α and interleukin-17A, with the goal of achieving greater clinical efficacy than can be achieved by blocking either cytokine alone. This work characterized the pharmacokinetics of ABT-122 in healthy subjects and in patients with rheumatoid arthritis. METHODS: ABT-122 pharmacokinetics was evaluated in three phase I studies. In Study 1, single intravenous (0...
May 2018: Clinical Pharmacokinetics
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
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