Monoclonal antibodies against metzincin targets.

Published on Jan 1, 2019in British Journal of Pharmacology7.73
· DOI :10.1111/BPH.14186
Salvatore Santamaria14
Estimated H-index: 14
(Imperial College London),
Rens de Groot9
Estimated H-index: 9
(Imperial College London)
The metzincin clan of metalloproteinases includes the MMP, ADAM and ADAMTS families, which cleave extracellular targets in a wide range of (patho)physiological processes. Antibodies constitute a powerful tool to modulate the activity of these enzymes for both therapeutic and research purposes. In this review, we give an overview of monoclonal antibodies (mAbs) that have been tested in preclinical disease models, human trials and important studies of metzincin structure and function. Initial attempts to develop therapeutic small molecule inhibitors against MMPs were hampered by structural similarities between metzincin active sites and, consequently, off-target effects. Therefore, more recently, mAbs have been developed that do not bind to the active site but bind to surface-exposed loops that are poorly conserved in closely related family members. Inhibition of protease activity by these mAbs occurs through a variety of mechanisms, including 1) barring access to the active site 2) disruption of exosite binding and 3) prevention of protease activation. These different modes of inhibition are discussed in the context of the antibodies’ potency, selectivity and, importantly, the effects in models of disease and clinical trials. In addition, various innovative strategies that were used to generate anti-metzincin mAbs are discussed.
📖 Papers frequently viewed together
208 Citations
966 Citations
33 Citations
#1Simon D. Harding (Edin.: University of Edinburgh)H-Index: 21
#2Joanna L. Sharman (Edin.: University of Edinburgh)H-Index: 41
Last. Nc-IupharH-Index: 5
view all 18 authors...
The IUPHAR/BPS Guide to PHARMACOLOGY (GtoPdb, and its precursor IUPHAR-DB, have captured expert-curated interactions between targets and ligands from selected papers in pharmacology and drug discovery since 2003. This resource continues to be developed in conjunction with the International Union of Basic and Clinical Pharmacology (IUPHAR) and the British Pharmacological Society (BPS). As previously described, our unique model of content selection and quality control ...
1,300 CitationsSource
#1Jacob Lund (Novo Nordisk)H-Index: 4
#2Anne Mette Elimar Bitsch (Novo Nordisk)H-Index: 1
Last. Helle Heibroch Petersen (Novo Nordisk)H-Index: 8
view all 9 authors...
Decysin-1 (ADAMDEC1) is an orphan ADAM-like metalloprotease with unknown biological function and a short domain structure. ADAMDEC1 mRNA has previously been demonstrated primarily in macrophages and mature dendritic cells. Here, we generated monoclonal antibodies (mAbs) against the mature ADAMDEC1 protein, as well as mAbs specific for the ADAMDEC1 pro-form, enabling further investigations of the metalloprotease. The generated mAbs bind ADAMDEC1 with varying affinity and represent at least six di...
3 CitationsSource
#1Jie Ye (UM: University of Macau)H-Index: 1
#1Jie Ye (UM: University of Macau)H-Index: 2
Last. Hang Fai Kwok (UM: University of Macau)H-Index: 23
view all 5 authors...
Abstract Pancreatic ductal adenocarcinoma (PDAC) is one of the most lethal types of tumor amongst all human cancers due to late diagnosis and resistant to treatment with chemotherapy and radiation. Preclinical and clinical studies have revealed that ErbB family for example epidermal growth factor receptor (EGFR) is a validated molecular target for pancreatic cancer prevention and therapy. The ErbB signaling cascade is regulated by a member of the ADAM (a disintegrin and metalloprotease) family, ...
10 CitationsSource
#1Stephen P.H. Alexander (University of Nottingham)H-Index: 67
#2Doriano FabbroH-Index: 92
Last. Jamie A. Davies (Edin.: University of Edinburgh)H-Index: 61
view all 11 authors...
The Concise Guide to PHARMACOLOGY 2017/18 provides concise overviews of the key properties of nearly 1800 human drug targets with an emphasis on selective pharmacology (where available), plus links to an open access knowledgebase of drug targets and their ligands (, which provides more detailed views of target and ligand properties. Although the Concise Guide represents approximately 400 pages, the material presented is substantially reduced compared to information an...
581 CitationsSource
#1Parker G. Jobin (UBC: University of British Columbia)H-Index: 4
#2Georgina S. Butler (UBC: University of British Columbia)H-Index: 35
Last. Christopher M. Overall (UBC: University of British Columbia)H-Index: 99
view all 3 authors...
Abstract Adaption of a single protein to perform multiple independent functions facilitates functional plasticity of the proteome allowing a limited number of protein-coding genes to perform a multitude of cellular processes. Multifunctionality is achievable by post-translational modifications and by modulating subcellular localization. Matrix metalloproteinases (MMPs), classically viewed as degraders of the extracellular matrix (ECM) responsible for matrix protein turnover, are more recently re...
69 CitationsSource
#1C Y Yang (Arthritis Research UK)H-Index: 1
#2Anastasios Chanalaris (Arthritis Research UK)H-Index: 15
Last. Linda Troeberg (Arthritis Research UK)H-Index: 28
view all 3 authors...
Summary Introduction Matrix metalloproteinases (MMPs) and ‘aggrecanase' a disintegrin and metalloproteinase with thrombospondin motifs (ADAMTSs) are well established to play key roles in osteoarthritis (OA) through degradation of extracellular matrix (ECM) type II collagen and aggrecan, and are thus potential targets for development of OA therapies. Objective This paper aims to provide a comprehensive review of the expression and potential roles of other, lesser-known ADAMTSs and related adamaly...
90 CitationsSource
#1Todd ApplebyH-Index: 9
Last. Hyock Joo KwonH-Index: 20
view all 14 authors...
Abstract Matrix metalloproteinase 9 (MMP9) is a member of a large family of proteases that are secreted as inactive zymogens. It is a key regulator of the extracellular matrix, involved in the degradation of various extracellular matrix proteins. MMP9 plays a pathological role in a variety of inflammatory and oncology disorders and has long been considered an attractive therapeutic target. GS-5745, a potent, highly selective humanized monoclonal antibody inhibitor of MMP9, has shown promise in t...
41 CitationsSource
#1Salvatore Santamaria (University of Oxford)H-Index: 14
#2Oleg Fedorov (SGC: Structural Genomics Consortium)H-Index: 51
Last. Kazuhiro Yamamoto (University of Oxford)H-Index: 17
view all 7 authors...
ABSTRACTThe potent aggrecanase ADAMTS-5 is constitutively secreted by chondrocytes, but it is rapidly endocytosed in normal cartilage via the cell surface endocytic receptor LRP1. Therefore it is difficult to detect the total ADAMTS-5 activity produced. In this study, we isolated a monoclonal anti-ADAMTS-5 antibody 1B7 that blocks LRP1-mediated internalization without affecting the aggrecanolytic activity. Addition of 1B7 to cultured human chondrocytes revealed the full aggrecanolytic activity o...
5 CitationsSource
#1Dong Hyun Nam (UCR: University of California, Riverside)H-Index: 11
#2Kuili Fang (UCR: University of California, Riverside)H-Index: 4
Last. Xin Ge (UCR: University of California, Riverside)H-Index: 14
view all 5 authors...
: Matrix metalloproteinase-14 (MMP-14) plays important roles in cancer metastasis, and the failures of broad-spectrum MMP compound inhibitors in clinical trials suggested selectivity is critical. By grafting an MMP-14 specific inhibition motif into complementarity determining region (CDR)-H3 of antibody scaffolds and optimizing other CDRs and the sequences that flank CDR-H3, we isolated a Fab 1F8 showing a binding affinity of 8.3 nM with >1000-fold enhancement on inhibition potency compared to t...
12 CitationsSource
#1Kazuhiro YamamotoH-Index: 17
Last. Hideaki NagaseH-Index: 103
view all 8 authors...
Objectives: The aggrecanase ADAMTS-5 and the collagenase MMP-13 are constitutively secreted by chondrocytes in normal cartilage, but rapidly endocytosed via the cell surface endocytic receptor low-density lipoprotein receptor-related protein 1 (LRP1) and subsequently degraded. This endocytic system is impaired in osteoarthritic (OA) cartilage due to increased ectodomain ‘shedding' of LRP1. The aim of this study is to identify the LRP1 sheddase(s) in human cartilage, and to test whether inhibitio...
27 CitationsSource
Cited By22
#1Taiji MizoguchiH-Index: 2
#2Bryan T. MacDonald (Broad Institute)H-Index: 25
Last. Virendar K. Kaushik (Broad Institute)H-Index: 8
view all 12 authors...
Rationale: Despite contemporary therapy, coronary artery disease (CAD) remains a leading cause of mortality. Genetic variants at ADAMTS7 have been associated with CAD and the loss of ADAMTS7 is protective for atherosclerosis. ADAMTS7 (a disintegrin and metalloproteinase with thrombospondin motifs 7) is a secreted metalloproteinase and complex proteoglycan, yet the mechanism linking ADAMTS7 to CAD risk remains unresolved. Objective: To investigate the role of ADAMTS7 catalytic function in vascula...
1 CitationsSource
Proteases play a crucial role in the progression and metastasis of ovarian cancer. Pericellular protein degradation and fragmentation along with remodeling of the extracellular matrix (ECM) is accomplished by numerous proteases that are present in the ovarian tumor microenvironment. Several proteolytic processes have been linked to cancer progression, particularly those facilitated by the matrix metalloproteinase (MMP) family. These proteases have been linked to enhanced migratory ability, extra...
1 CitationsSource
The hyalectan family is composed of the proteoglycans aggrecan, versican, brevican and neurocan. Hyalectans, also known as lecticans, are components of the extracellular matrix of different tissues and play essential roles in key biological processes including skeletal development, and they are related to the correct maintenance of the vascular and central nervous system. For instance, hyalectans participate in the organization of structures such as perineural nets and in the regulation of neuri...
1 CitationsSource
#1Salvatore Santamaria (Imperial College London)H-Index: 14
#2Doretta Cuffaro (UniPi: University of Pisa)H-Index: 5
Last. Josefin Ahnström (Imperial College London)H-Index: 16
view all 10 authors...
ADAMTS-5 is a major protease involved in the turnover of proteoglycans such as aggrecan and versican. Dysregulated aggrecanase activity of ADAMTS-5 has been directly linked to the etiology of osteoarthritis (OA). For this reason, ADAMTS-5 is a pharmaceutical target for the treatment of OA. ADAMTS-5 shares high structural and functional similarities with ADAMTS-4, which makes the design of selective inhibitors particularly challenging. Here we exploited the ADAMTS-5 binding capacity of β-N-acetyl...
4 CitationsSource
#1Jess Pedrina (Deakin University)
#2John Stambas (Deakin University)H-Index: 24
Each year, hundreds of thousands of individuals succumb to influenza virus infection and its associated complications. Several preventative and therapeutic options may be applied in order to preserve life. These traditional approaches include administration of seasonal influenza vaccines, pharmacological interventions in the form of antiviral drug therapy and supportive clinical approaches including mechanical ventilation and extracorporeal membrane oxygenation. While these measures have shown v...
#1Stefano Pluda (Ca' Foscari University of Venice)H-Index: 3
#2Ylenia Mazzocato (Ca' Foscari University of Venice)
Last. Alessandro Angelini (Ca' Foscari University of Venice)H-Index: 18
view all 3 authors...
ADAM and ADAMTS are two large metalloproteinase families involved in numerous physiological processes, such as shedding of cell-surface protein ectodomains and extra-cellular matrix remodelling. Aberrant expression or dysregulation of ADAMs and ADAMTSs activity has been linked to several pathologies including cancer, inflammatory, neurodegenerative and cardiovascular diseases. Inhibition of ADAM and ADAMTS metalloproteinases have been attempted using various small molecules and protein-based the...
#1Lejian Jiang (ZJU: Zhejiang University)
#2Jiachen Lin (Peking Union Medical College Hospital)H-Index: 3
Last. Mao LinH-Index: 7
view all 10 authors...
#1Salvatore Santamaria (Imperial College London)H-Index: 14
#2Rens de Groot (UCL: University College London)H-Index: 9
Last. Rens de Groot (UCL: University College London)H-Index: 1
view all 2 authors...
The a disintegrin-like and metalloproteinase with thrombospondin motif (ADAMTS) family comprises 19 proteases that regulate the structure and function of extracellular proteins in the extracellular...
5 CitationsSource
#1Hongyue Wang (Peking Union Medical College)H-Index: 1
#2Longjian Huang (Peking Union Medical College)H-Index: 5
Last. Ying Peng (Peking Union Medical College)H-Index: 21
view all 7 authors...
Alzheimer Disease (AD) is the most prevalent type of dementia. Pathological changes in the AD brain include Amyloid β-protein (Aβ) plaques and Neurofibrillary Tangles (NFTs), as well as extensive neuronal and synaptic loss. Matrix Metalloproteinase-2 (MMP-2) is a neutral, zinc-dependent protease that primarily targets extracellular matrix proteins. MMP-2 activity is strictly controlled, and its dysregulation has been implicated in a variety of pathologies, including AD. In this brief review, we ...
1 CitationsSource
#1Salvatore Santamaria (Imperial College London)H-Index: 14
#2Doretta Cuffaro (UniPi: University of Pisa)H-Index: 5
Last. Josefin Ahnstroem (Imperial College London)
view all 10 authors...
ADAMTS-5 is a major protease involved in the turnover of proteoglycans such as aggrecan and versican. Its aggrecanase activity has been directly linked to the etiology of osteoarthritis (OA), identifying ADAMTS-5 as a pharmaceutical target for OA treatment. However, most existing ADAMTS-5 inhibitors target its active site and therefore suffer from poor selectivity. Here, using a novel approach, we have designed a new class of sugar-based arylsulfonamide inhibitors, which are selective for ADAMTS...