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Article ; Online: Imaging the Alternatively Spliced D Domain of Tenascin C in a Preclinical Model of Inflammatory Bowel Disease.

Zhang, Liang / Wang, Yuzhen / Homan, Kristoff T / Gaudette, Stephanie M / McCluskey, Andrew J / Chan, Ying / Murphy, Joanne / Abdalla, Mary / Nelson, Christine M / Sun, Victor Z / Erickson, Jamie E / Knight, Heather L / Clabbers, Anca / Sterman, Annette J Schwartz / Mitra, Soumya

Molecular imaging and biology

2022 Volume 25, Issue 2, Page(s) 314–323

Abstract: Purpose: To image colon-expressed alternatively spliced D domain of tenascin C in preclinical colitis models using near infrared (NIR)-labeled targeted molecular imaging agents.: Procedures: A human IgG1 with nanomolar binding affinity specific to ... ...

Abstract	Purpose: To image colon-expressed alternatively spliced D domain of tenascin C in preclinical colitis models using near infrared (NIR)-labeled targeted molecular imaging agents. Procedures: A human IgG1 with nanomolar binding affinity specific to the alternatively spliced D domain of tenascin C was generated. Immunohistochemistry identified disease-specific expression of this extracellular matrix protein in the colon of mice given dextran sulfate sodium in the drinking water. The antibody reagent was labeled with the NIR fluorophore IRDye 800CW via amine chemistry and intravenously dosed to evaluate in vivo targeting specificity. Increasing doses of imaging agent were given to estimate the saturating dose. Results: The NIR-labeled proteins successfully targeted colonic lesions in a murine model of colitis. Co-administration of a molar excess competing unlabeled dose reduced normalized uptake in diseased colon by > 70%. Near infrared ex vivo images of colon resected from diseased animals showed saturation at doses exceeding 1 nmol and was confirmed with additional quantitative ex vivo biodistribution. Cellular-level specificity and protein stability were assessed via microscopy. Conclusions: Our imaging data suggest the alternatively spliced D domain of tenascin C is a promising target for delivery-based applications in inflammatory bowel diseases.
MeSH term(s)	Humans ; Animals ; Mice ; Tenascin ; Tissue Distribution ; Inflammatory Bowel Diseases ; Colitis/pathology
Chemical Substances	Tenascin
Language	English
Publishing date	2022-07-29
Publishing country	United States
Document type	Journal Article
ZDB-ID	2079160-4
ISSN	1860-2002 ; 1536-1632
ISSN (online)	1860-2002
ISSN	1536-1632
DOI	10.1007/s11307-022-01758-6
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Article ; Online: Comparison of the in vitro and in vivo stability of a succinimide intermediate observed on a therapeutic IgG1 molecule.

Ouellette, David / Chumsae, Chris / Clabbers, Anca / Radziejewski, Czeslaw / Correia, Ivan

mAbs

2013 Volume 5, Issue 3, Page(s) 432–444

Abstract: Deamidation of asparagine residues, a post-translational modification observed in proteins, is a common degradation pathway in monoclonal antibodies (mAbs). The kinetics of deamidation is influenced by primary sequence as well as secondary and tertiary ... ...

Abstract	Deamidation of asparagine residues, a post-translational modification observed in proteins, is a common degradation pathway in monoclonal antibodies (mAbs). The kinetics of deamidation is influenced by primary sequence as well as secondary and tertiary folding. Analytical hydrophobic interaction chromatography (HIC) is used to evaluate hydrophobicity of candidate mAbs and uncover post-translational modifications. Using HIC, we discovered atypical heterogeneity in a highly hydrophobic molecule (mAb-1). Characterization of the different HIC fractions using LC/MS/MS revealed a stable succinimide intermediate species localized to an asparagine-glycine motif in the heavy chain binding region. The succinimide intermediate was stable in vitro at pH 7 and below and increased on storage at 25°C and 40°C. Biacore evaluation showed a decrease in binding affinity of the succinimide intermediate compared with the native asparagine molecule. In vivo studies of mAb-1 recovered from a pharmacokinetic study in cynomolgus monkeys revealed an unstable succinimide species and rapid conversion to aspartic/iso-aspartic acid. Mutation from asparagine to aspartic acid led to little loss in affinity. This study illustrates the importance of evaluating modifications of therapeutic mAbs both in vitro and in serum, the intended environment of the molecule. Potential mechanisms that stabilize the succinimide intermediate in vitro are discussed.
MeSH term(s)	Amino Acid Motifs ; Animals ; Antibody Affinity ; Asparagine/blood ; Asparagine/chemistry ; Binding Sites, Antibody ; Chromatography ; Epitope Mapping ; Glycine/blood ; Glycine/chemistry ; Hydrogen-Ion Concentration ; Hydrophobic and Hydrophilic Interactions ; Immunoglobulin G/blood ; Immunoglobulin G/chemistry ; Immunoglobulin Heavy Chains/blood ; Immunoglobulin Heavy Chains/chemistry ; Immunotherapy ; In Vitro Techniques ; Macaca fascicularis ; Protein Binding ; Protein Processing, Post-Translational ; Protein Stability ; Succinimides/blood ; Succinimides/chemistry ; Tandem Mass Spectrometry
Chemical Substances	Immunoglobulin G ; Immunoglobulin Heavy Chains ; Succinimides ; succinimide (10X90O3503) ; Asparagine (7006-34-0) ; Glycine (TE7660XO1C)
Language	English
Publishing date	2013-04-22
Publishing country	United States
Document type	Comparative Study ; Journal Article
ZDB-ID	2537838-7
ISSN	1942-0870 ; 1942-0870
ISSN (online)	1942-0870
ISSN	1942-0870
DOI	10.4161/mabs.24458
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Article ; Online: IL11-mediated stromal cell activation may not be the master regulator of pro-fibrotic signaling downstream of TGFβ.

Tan, Yunhao / Mosallanejad, Kenta / Zhang, Qingxiu / O'Brien, Stephen / Clements, Meghan / Perper, Stuart / Wilson, Sarah / Chaulagain, Sudiksha / Wang, Jing / Abdalla, Mary / Al-Saidi, Helen / Butt, Danyal / Clabbers, Anca / Ofori, Kwasi / Dillon, Beth / Harvey, Bohdan / Memmott, John / Negron, Christopher / Winarta, David /

Tan, Catherine / Biswas, Amlan / Dong, Feng / Morales-Tirado, Vanessa / Lu, Xiaoqing / Singh, Gurminder / White, Michael / Ashley, Shanna / Knight, Heather / Westmoreland, Susan / Phillips, Lucy / Carr, Tracy / Reinke-Breen, Lauren / Singh, Rajeeva / Xu, Jianwen / Wu, Kan / Rinaldi, Lisa / Stoll, Brian / He, Yupeng David / Hazelwood, Lisa / Karman, Jozsef / McCluskey, Andrew / Stine, William / Correia, Ivan / Gauld, Stephen / Levesque, Marc C / Veldman, Geertruida / Hubeau, Cedric / Radstake, Timothy / Sadhukhan, Ramkrishna / Fiebiger, Edda

Frontiers in immunology

2024 Volume 15, Page(s) 1293883

Abstract: Fibrotic diseases, such as idiopathic pulmonary fibrosis (IPF) and systemic scleroderma (SSc), are commonly associated with high morbidity and mortality, thereby representing a significant unmet medical need. Interleukin 11 (IL11)-mediated cell ... ...

Abstract	Fibrotic diseases, such as idiopathic pulmonary fibrosis (IPF) and systemic scleroderma (SSc), are commonly associated with high morbidity and mortality, thereby representing a significant unmet medical need. Interleukin 11 (IL11)-mediated cell activation has been identified as a central mechanism for promoting fibrosis downstream of TGFβ. IL11 signaling has recently been reported to promote fibroblast-to-myofibroblast transition, thus leading to various pro-fibrotic phenotypic changes. We confirmed increased mRNA expression of IL11 and IL11Rα in fibrotic diseases by OMICs approaches and
MeSH term(s)	Humans ; Transforming Growth Factor beta/metabolism ; Interleukin-11 ; Signal Transduction ; Fibrosis ; Myofibroblasts/metabolism
Chemical Substances	Transforming Growth Factor beta ; Interleukin-11
Language	English
Publishing date	2024-02-22
Publishing country	Switzerland
Document type	Journal Article ; Research Support, Non-U.S. Gov't
ZDB-ID	2606827-8
ISSN	1664-3224 ; 1664-3224
ISSN (online)	1664-3224
ISSN	1664-3224
DOI	10.3389/fimmu.2024.1293883
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Article ; Online: Structural basis for continued antibody evasion by the SARS-CoV-2 receptor binding domain.

Nabel, Katherine G / Clark, Sarah A / Shankar, Sundaresh / Pan, Junhua / Clark, Lars E / Yang, Pan / Coscia, Adrian / McKay, Lindsay G A / Varnum, Haley H / Brusic, Vesna / Tolan, Nicole V / Zhou, Guohai / Desjardins, Michaël / Turbett, Sarah E / Kanjilal, Sanjat / Sherman, Amy C / Dighe, Anand / LaRocque, Regina C / Ryan, Edward T /

Tylek, Casey / Cohen-Solal, Joel F / Darcy, Anhdao T / Tavella, Davide / Clabbers, Anca / Fan, Yao / Griffiths, Anthony / Correia, Ivan R / Seagal, Jane / Baden, Lindsey R / Charles, Richelle C / Abraham, Jonathan

Science (New York, N.Y.)

2022 Volume 375, Issue 6578, Page(s) eabl6251

Abstract: Many studies have examined the impact of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) variants on neutralizing antibody activity after they have become dominant strains. Here, we evaluate the consequences of further viral evolution. We ... ...

Abstract	Many studies have examined the impact of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) variants on neutralizing antibody activity after they have become dominant strains. Here, we evaluate the consequences of further viral evolution. We demonstrate mechanisms through which the SARS-CoV-2 receptor binding domain (RBD) can tolerate large numbers of simultaneous antibody escape mutations and show that pseudotypes containing up to seven mutations, as opposed to the one to three found in previously studied variants of concern, are more resistant to neutralization by therapeutic antibodies and serum from vaccine recipients. We identify an antibody that binds the RBD core to neutralize pseudotypes for all tested variants but show that the RBD can acquire an N-linked glycan to escape neutralization. Our findings portend continued emergence of escape variants as SARS-CoV-2 adapts to humans.
MeSH term(s)	Angiotensin-Converting Enzyme 2/chemistry ; Angiotensin-Converting Enzyme 2/metabolism ; Antibodies, Neutralizing/immunology ; Antibodies, Viral/immunology ; BNT162 Vaccine/immunology ; Betacoronavirus/immunology ; COVID-19/immunology ; COVID-19/virology ; Cross Reactions ; Cryoelectron Microscopy ; Crystallography, X-Ray ; Epitopes ; Evolution, Molecular ; Humans ; Immune Evasion ; Models, Molecular ; Mutation ; Polysaccharides/analysis ; Protein Binding ; Protein Domains ; Receptors, Coronavirus/chemistry ; Receptors, Coronavirus/metabolism ; SARS-CoV-2/genetics ; SARS-CoV-2/immunology ; Spike Glycoprotein, Coronavirus/chemistry ; Spike Glycoprotein, Coronavirus/genetics ; Spike Glycoprotein, Coronavirus/immunology ; Viral Pseudotyping
Chemical Substances	Antibodies, Neutralizing ; Antibodies, Viral ; Epitopes ; Polysaccharides ; Receptors, Coronavirus ; Spike Glycoprotein, Coronavirus ; spike glycoprotein, SARS-CoV ; spike protein, SARS-CoV-2 ; ACE2 protein, human (EC 3.4.17.23) ; Angiotensin-Converting Enzyme 2 (EC 3.4.17.23) ; BNT162 Vaccine (N38TVC63NU)
Language	English
Publishing date	2022-01-21
Publishing country	United States
Document type	Journal Article ; Research Support, N.I.H., Extramural
ZDB-ID	128410-1
ISSN	1095-9203 ; 0036-8075
ISSN (online)	1095-9203
ISSN	0036-8075
DOI	10.1126/science.abl6251
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Article ; Online: Generation and characterization of ABBV642, a dual variable domain immunoglobulin molecule (DVD-Ig) that potently neutralizes VEGF and PDGF-BB and is designed for the treatment of exudative age-related macular degeneration.

Ding, Kun / Eaton, Lucia / Bowley, Diana / Rieser, Matthew / Chang, Qing / Harris, Maria C / Clabbers, Anca / Dong, Feng / Shen, Jikui / Hackett, Sean F / Touw, Debra S / Bixby, Jacqueline / Zhong, Suju / Benatuil, Lorenzo / Bose, Sahana / Grinnell, Christine / Preston, Gregory M / Iyer, Ramesh / Sadhukhan, Ramkrishna /

Marchie, Susan / Overmeyer, Gary / Ghayur, Tariq / van Riet, Deborah A / Tang, Shibo / Campochario, Peter A / Gu, Jijie

mAbs

2017 Volume 9, Issue 2, Page(s) 269–284

Abstract: 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 ... ...

Abstract	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. We generated a dual variable domain immunoglobulin molecule, ABBV642 that specifically and potently binds and neutralizes VEGF and PDGF-BB. ABBV642 has been optimized for treatment of exudative AMD based on the following design characteristics: 1) high affinity binding to all VEGF-A isoforms and both soluble and extracellular matrix (ECM)-associated PDGF-BB; 2) potential for extended residence time in the vitreous cavity to decrease the frequency of intraocular injections; 3) rapid clearance from systemic circulation compared with molecules with wild type Fc region for normal FcRn binding, which may reduce the risk of systemic complications; and 4) low risk of potential effector function. The bispecificity of ABBV642 allows for a single injection of a single therapeutic agent, and thus a more streamlined development and regulatory path compared with combination products. In a mouse model of exudative AMD, ABBV642 was observed to be more effective than aflibercept. ABBV642 has potential to improve efficacy with reduced injection frequency in patients with exudative AMD, thereby reducing the enormous disease burden for patients and society.
Language	English
Publishing date	2017-02
Publishing country	United States
Document type	Journal Article
ISSN	1942-0870
ISSN (online)	1942-0870
DOI	10.1080/19420862.2016.1268305
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Article: Comparative analysis of various in vitro COT kinase assay formats and their applications in inhibitor identification and characterization.

Jia, Yong / Quinn, Christopher M / Clabbers, Anca / Talanian, Robert / Xu, Yajun / Wishart, Neil / Allen, Hamish

Analytical biochemistry

2006 Volume 350, Issue 2, Page(s) 268–276

Abstract: Cancer osaka thyroid (COT) is a member of the mitogen-activated protein kinase kinase kinase family of enzymes and plays a pivotal role in tumor necrosis factor-alpha production in macrophages. Consequently, COT is considered to be a promising target for ...

Abstract	Cancer osaka thyroid (COT) is a member of the mitogen-activated protein kinase kinase kinase family of enzymes and plays a pivotal role in tumor necrosis factor-alpha production in macrophages. Consequently, COT is considered to be a promising target for antiinflammatory drug discovery. We describe here the development of in vitro COT assays in several formats and the advantages and disadvantages of each. A cascade assay requires very small amounts of enzyme and can provide a useful tool for high-throughput screening, but it is not desirable for compound mechanistic studies due to complicated kinetics. Direct assays are superior to cascade assays and are suitable for both compound screening and mechanistic studies. Among the direct assays, the homogeneous time-resolved fluorescence (HTRF) format is preferred over the radiometric format due to the robustness, throughput, and ease of use of the HTRF format. When the physiological protein substrate MEK1 (MAP/Erk kinase 1) was used to determine inhibitor potencies, false positives were observed due to compound interference by binding to MEK1. Using a MEK1 peptide substrate, these false positives were eliminated. In addition, we describe a simple method to study the ATP competitiveness of compounds. The knowledge gained through our studies with COT, and the methods described for our assays and compound mechanistic studies, can be readily applied to other kinase targets.
MeSH term(s)	Adenosine Triphosphate/metabolism ; Fluorescence ; Humans ; Kinetics ; MAP Kinase Kinase 1/metabolism ; MAP Kinase Kinase Kinases/analysis ; MAP Kinase Kinase Kinases/antagonists & inhibitors ; MAP Kinase Signaling System ; Phosphorus Radioisotopes ; Proto-Oncogene Proteins/analysis ; Proto-Oncogene Proteins/antagonists & inhibitors
Chemical Substances	Phosphorus Radioisotopes ; Proto-Oncogene Proteins ; Adenosine Triphosphate (8L70Q75FXE) ; MAP Kinase Kinase Kinases (EC 2.7.11.25) ; MAP3K8 protein, human (EC 2.7.11.25) ; MAP Kinase Kinase 1 (EC 2.7.12.2)
Language	English
Publishing date	2006-03-15
Publishing country	United States
Document type	Comparative Study ; Evaluation Studies ; Journal Article
ZDB-ID	1110-1
ISSN	1096-0309 ; 0003-2697
ISSN (online)	1096-0309
ISSN	0003-2697
DOI	10.1016/j.ab.2005.11.010
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Article ; Online: Identification of a selective thieno[2,3-c]pyridine inhibitor of COT kinase and TNF-alpha production.

Bioorganic & medicinal chemistry letters

2009 Volume 19, Issue 6, Page(s) 1722–1725

Abstract: COT (Tpl2 in mice) is a serine/threonine MAP3 kinase that regulates production of TNF-alpha and other pro-inflammatory cytokines such as IL-1beta via the ERK/MAP kinase pathway. As TNF-alpha and IL-1beta are clinically validated targets for therapeutic ... ...

Abstract	COT (Tpl2 in mice) is a serine/threonine MAP3 kinase that regulates production of TNF-alpha and other pro-inflammatory cytokines such as IL-1beta via the ERK/MAP kinase pathway. As TNF-alpha and IL-1beta are clinically validated targets for therapeutic intervention in rheumatoid arthritis (RA), blocking COT provides a potential avenue for amelioration of disease. Herein we describe identification of a cellular active selective small molecule inhibitor of COT kinase.
MeSH term(s)	Animals ; Arthritis, Rheumatoid/drug therapy ; Chemistry, Pharmaceutical/methods ; Drug Design ; Enzyme Inhibitors/chemical synthesis ; Enzyme Inhibitors/pharmacology ; Extracellular Signal-Regulated MAP Kinases/metabolism ; Humans ; Hydrogen Bonding ; Inhibitory Concentration 50 ; Interleukin-1beta/metabolism ; Ligands ; MAP Kinase Kinase Kinases/antagonists & inhibitors ; MAP Kinase Kinase Kinases/chemistry ; Mice ; Molecular Structure ; Proto-Oncogene Proteins/antagonists & inhibitors ; Proto-Oncogene Proteins/chemistry ; Pyridines/chemical synthesis ; Pyridines/pharmacology ; Tumor Necrosis Factor-alpha/antagonists & inhibitors ; Tumor Necrosis Factor-alpha/chemistry ; Tumor Necrosis Factor-alpha/metabolism
Chemical Substances	Enzyme Inhibitors ; Interleukin-1beta ; Ligands ; Proto-Oncogene Proteins ; Pyridines ; Tumor Necrosis Factor-alpha ; thienopyridine ; Extracellular Signal-Regulated MAP Kinases (EC 2.7.11.24) ; MAP Kinase Kinase Kinases (EC 2.7.11.25) ; MAP3K8 protein, human (EC 2.7.11.25)
Language	English
Publishing date	2009-03-15
Publishing country	England
Document type	Journal Article
ZDB-ID	1063195-1
ISSN	1464-3405 ; 0960-894X
ISSN (online)	1464-3405
ISSN	0960-894X
DOI	10.1016/j.bmcl.2009.01.088
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Article ; Online: Discovery of thieno[2,3-c]pyridines as potent COT inhibitors.

George, Dawn / Friedman, Michael / Allen, Hamish / Argiriadi, Maria / Barberis, Claude / Bischoff, Agnieszka / Clabbers, Anca / Cusack, Kevin / Dixon, Richard / Fix-Stenzel, Shannon / Gordon, Thomas / Janssen, Bernd / Jia, Yong / Moskey, Maria / Quinn, Christopher / Salmeron, Jose-Andres / Wishart, Neil / Woller, Kevin / Yu, Zhengtian

Bioorganic & medicinal chemistry letters

2008 Volume 18, Issue 18, Page(s) 4952–4955

Abstract: Evaluation of hit chemotypes from high throughput screening identified a novel series of 2,4-disubstituted thieno[2,3-c]pyridines as COT kinase inhibitors. Structural modifications exploring SAR at the 2- and 4-positions resulting in inhibitors with ... ...

Abstract	Evaluation of hit chemotypes from high throughput screening identified a novel series of 2,4-disubstituted thieno[2,3-c]pyridines as COT kinase inhibitors. Structural modifications exploring SAR at the 2- and 4-positions resulting in inhibitors with improved enzyme potency and cellular activity are disclosed.
MeSH term(s)	Combinatorial Chemistry Techniques ; Crystallography, X-Ray ; Humans ; MAP Kinase Kinase Kinases/antagonists & inhibitors ; Models, Molecular ; Molecular Conformation ; Molecular Structure ; Proto-Oncogene Proteins/antagonists & inhibitors ; Pyridines/chemical synthesis ; Pyridines/chemistry ; Pyridines/pharmacology ; Structure-Activity Relationship ; Thiophenes/chemical synthesis ; Thiophenes/chemistry ; Thiophenes/pharmacology
Chemical Substances	Proto-Oncogene Proteins ; Pyridines ; Thiophenes ; MAP Kinase Kinase Kinases (EC 2.7.11.25) ; MAP3K8 protein, human (EC 2.7.11.25)
Language	English
Publishing date	2008-09-15
Publishing country	England
Document type	Journal Article
ZDB-ID	1063195-1
ISSN	1464-3405 ; 0960-894X
ISSN (online)	1464-3405
ISSN	0960-894X
DOI	10.1016/j.bmcl.2008.08.037
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Article: Purification and kinetic characterization of recombinant human mitogen-activated protein kinase kinase kinase COT and the complexes with its cellular partner NF-kappa B1 p105.

Jia, Yong / Quinn, Christopher M / Bump, Nancy J / Clark, Kevin M / Clabbers, Anca / Hardman, Jennifer / Gagnon, Andrew / Kamens, Joanne / Tomlinson, Medha J / Wishart, Neil / Allen, Hamish

Archives of biochemistry and biophysics

2005 Volume 441, Issue 1, Page(s) 64–74

Abstract: Cancer osaka thyroid (COT), a human MAP 3 K, is essential for lipopolysaccharide activation of the Erk MAPK cascade in macrophages. COT 30--467 is insoluble, whereas low levels of COT 30--397 can be expressed, but this protein is unstable. However, both ... ...

Abstract	Cancer osaka thyroid (COT), a human MAP 3 K, is essential for lipopolysaccharide activation of the Erk MAPK cascade in macrophages. COT 30--467 is insoluble, whereas low levels of COT 30--397 can be expressed, but this protein is unstable. However, both COT 30--467 and COT 30--397 are expressed in a soluble and stable form when produced in complex with the C-terminal half of p105. The k(cat) of COT 30--397 is reduced approximately 47--fold in the COT 30--467/p105 Delta N complex. COT prefers Mn(2+) to Mg(2+) as the ATP metal cofactor, exhibiting an unusually high ATP K(m) in the presence of Mg(2+). When using Mn(2+) as the cofactor, the ATP K(m) is reduced to a level typical of most kinases. In contrast, the binding affinity of COT for its other substrate MEK is cofactor independent. Our results using purified proteins indicate that p105 binding improves COT solubility and stability while down-regulating kinase activity, consistent with cellular data showing that p105 functions as an inhibitor of COT.
MeSH term(s)	Binding Sites ; Enzyme Activation ; Enzyme Stability ; Humans ; Jurkat Cells ; Kinetics ; MAP Kinase Kinase Kinases/chemistry ; MAP Kinase Kinase Kinases/genetics ; MAP Kinase Kinase Kinases/isolation & purification ; NF-kappa B/chemistry ; NF-kappa B p50 Subunit ; Protein Binding ; Protein Engineering/methods ; Protein Precursors/chemistry ; Proto-Oncogene Proteins/chemistry ; Proto-Oncogene Proteins/genetics ; Proto-Oncogene Proteins/isolation & purification ; Recombinant Proteins/chemistry ; Recombinant Proteins/isolation & purification ; Structure-Activity Relationship
Chemical Substances	NF-kappa B ; NF-kappa B p50 Subunit ; Protein Precursors ; Proto-Oncogene Proteins ; Recombinant Proteins ; MAP Kinase Kinase Kinases (EC 2.7.11.25) ; MAP3K8 protein, human (EC 2.7.11.25)
Language	English
Publishing date	2005-09-01
Publishing country	United States
Document type	Journal Article ; Research Support, Non-U.S. Gov't
ZDB-ID	523-x
ISSN	1096-0384 ; 0003-9861
ISSN (online)	1096-0384
ISSN	0003-9861
DOI	10.1016/j.abb.2005.06.020
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Article: Simultaneous targeting of multiple disease mediators by a dual-variable-domain immunoglobulin.

Wu, Chengbin / Ying, Hua / Grinnell, Christine / Bryant, Shaughn / Miller, Renee / Clabbers, Anca / Bose, Sahana / McCarthy, Donna / Zhu, Rong-Rong / Santora, Ling / Davis-Taber, Rachel / Kunes, Yune / Fung, Emma / Schwartz, Annette / Sakorafas, Paul / Gu, Jijie / Tarcsa, Edit / Murtaza, Anwar / Ghayur, Tariq

Nature biotechnology

2007 Volume 25, Issue 11, Page(s) 1290–1297

Abstract: For complex diseases in which multiple mediators contribute to overall disease pathogenesis by distinct or redundant mechanisms, simultaneous blockade of multiple targets may yield better therapeutic efficacy than inhibition of a single target. However, ... ...

Abstract	For complex diseases in which multiple mediators contribute to overall disease pathogenesis by distinct or redundant mechanisms, simultaneous blockade of multiple targets may yield better therapeutic efficacy than inhibition of a single target. However, developing two separate monoclonal antibodies for clinical use as combination therapy is impractical, owing to regulatory hurdles and cost. Multi-specific, antibody-based molecules have been investigated; however, their therapeutic use has been hampered by poor pharmacokinetics, stability and manufacturing feasibility. Here, we describe a generally applicable model of a dual-specific, tetravalent immunoglobulin G (IgG)-like molecule--termed dual-variable-domain immunoglobulin (DVD-Ig)--that can be engineered from any two monoclonal antibodies while preserving activities of the parental antibodies. This molecule can be efficiently produced from mammalian cells and exhibits good physicochemical and pharmacokinetic properties. Preclinical studies of a DVD-Ig protein in an animal disease model demonstrate its potential for therapeutic application in human diseases.
MeSH term(s)	Animals ; Antibodies, Bispecific/biosynthesis ; Antibodies, Bispecific/pharmacokinetics ; Antibodies, Bispecific/therapeutic use ; Antibodies, Monoclonal/biosynthesis ; Antibodies, Monoclonal/genetics ; Antibodies, Monoclonal/pharmacokinetics ; Antibodies, Monoclonal/therapeutic use ; Arthritis, Experimental/drug therapy ; Arthritis, Experimental/pathology ; CHO Cells ; Cricetinae ; Cricetulus ; Disease Models, Animal ; Humans ; Immunoglobulin Variable Region/biosynthesis ; Immunoglobulin Variable Region/genetics ; Immunoglobulin Variable Region/metabolism ; Immunoglobulin Variable Region/therapeutic use ; Interleukin-12/antagonists & inhibitors ; Interleukin-12/immunology ; Interleukin-18/antagonists & inhibitors ; Interleukin-18/immunology ; Mice ; Protein Engineering ; Protein Structure, Tertiary ; Rats
Chemical Substances	1D4.1-325 DVD-Ig protein ; Antibodies, Bispecific ; Antibodies, Monoclonal ; Immunoglobulin Variable Region ; Interleukin-18 ; Interleukin-12 (187348-17-0)
Language	English
Publishing date	2007-11
Publishing country	United States
Document type	Journal Article
ZDB-ID	1311932-1
ISSN	1546-1696 ; 1087-0156
ISSN (online)	1546-1696
ISSN	1087-0156
DOI	10.1038/nbt1345
Database	MEDical Literature Analysis and Retrieval System OnLINE

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Zs.A 2167: Show issues			Location: Je nach Verfügbarkeit (siehe Angabe bei Bestand) bis Jg. 1994: Bestellungen von Artikeln über das Online-Bestellformular Jg. 1995 - 2021: Lesesall (1.OG) ab Jg. 2022: Lesesaal (EG)
Zs.MO 137: Show issues
Zs.MG 43: Show issues

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