Last update 01 Nov 2024

S100A4

Last update 01 Nov 2024

Basic Info

Synonyms

18A2, 42A, calcium placental protein

+ [18]

Introduction

Calcium-binding protein that plays a role in various cellular processes including motility, angiogenesis, cell differentiation, apoptosis, and autophagy (PubMed:16707441, PubMed:23752197, PubMed:30713770). Increases cell motility and invasiveness by interacting with non-muscle myosin heavy chain (NMMHC) IIA/MYH9 (PubMed:16707441). Mechanistically, promotes filament depolymerization and increases the amount of soluble myosin-IIA, resulting in the formation of stable protrusions facilitating chemotaxis (By similarity). Modulates also the pro-apoptotic function of TP53 by binding to its C-terminal transactivation domain within the nucleus and reducing its protein levels (PubMed:23752197). Within the extracellular space, stimulates cytokine production including granulocyte colony-stimulating factor and CCL24 from T-lymphocytes (By similarity). In addition, stimulates T-lymphocyte chemotaxis by acting as a chemoattractant complex with PGLYRP1 that promotes lymphocyte migration via CCR5 and CXCR3 receptors (PubMed:30713770, PubMed:26654597).

Drugs associated with S100A4

AX-202

Target

S100A4

Mechanism

S100A4 inhibitors

Active Org.

Calluna Pharma, Inc. [+1]

Originator Org.

Arxx Therapeutics AS

Active Indication

Fibrosis [+2]

Inactive Indication-

Drug Highest PhasePhase 1

First Approval Ctry. / Loc.-

First Approval Date20 Jan 1800

LK-1

Target

S100A4

Mechanism

S100A4 inhibitors

Active Org.-

Originator Org.-

Active Indication

Solid tumor

Inactive Indication-

Drug Highest PhasePreclinical

First Approval Ctry. / Loc.-

First Approval Date20 Jan 1800

Targeted S100A4/TfR bispecific antibody(Houston Methodist)

Target

S100A4

Mechanism

S100A4 inhibitors

Active Org.

University of Texas Health Science Center at Houston [+1]

Originator Org.

University of Texas Health Science Center at Houston [+1]

Active Indication

Glioblastoma

Inactive Indication-

Drug Highest PhasePreclinical

First Approval Ctry. / Loc.-

First Approval Date20 Jan 1800

Clinical Trials associated with S100A4

NCT05965089 / RecruitingPhase 1

A First-in-human, Randomised Double-blind, Placebo-controlled 2-part Study to Evaluate the Safety, Tolerability, Immunogenicity and Pharmacokinetics of Single Ascending Doses of AX-202 in Healthy Subjects and Multiple Ascending Doses of AX-202 in Patients With Mild to Moderate Chronic Plaque Psoriasis.

The first-in-human study will be performed in healthy volunteers and patients with a chronic inflammatory skin disease. The primary objective is to evaluate the safety, tolerability and pharmacokinetics of increasing doses of AX-202 infusion.

Start Date25 Apr 2023

Sponsor / Collaborator

Arxx Therapeutics AS

NL-OMON35094 / CompletedNot Applicable

A Phase 1 Study to Compare the Pharmacokinetics of CAL-101 Capsules to Tablets in Healthy Male Subjects. - CAL-101 BE study.

Start Date09 Mar 2010

Sponsor / Collaborator

Calistoga Pharmaceuticals, Inc.

100 Clinical Results associated with S100A4

100 Translational Medicine associated with S100A4

0 Patents (Medical) associated with S100A4

1,765

Literatures (Medical) associated with S100A4

01 Jan 2025·Biochimica et Biophysica Acta (BBA) - Molecular Basis of Disease

S100A4 mediates the accumulation and functions of myeloid-derived suppressor cells via GP130/JAK2/STAT3 signaling in acute myeloid leukemia

Article

Author: Qi, Xiaolan ; Bai, Jingdi ; Guo, Pengxiang ; Dai, Yun ; Wu, ChangXue ; Hong, Wei ; Zeng, Zhu ; Zhang, Ting ; Xie, Xin ; Zhang, Jian ; Duan, Juanjuan ; Wang, Chanjuan ; Liang, Xinming ; Yu, Wenfeng ; Fu, Wenli ; Fan, Daogui ; Peng, Yuhui ; Zhou, Jing ; Li, Yi ; Zeng, Hongmei ; Chen, Pingping ; He, Yan ; Zhang, Qifang ; Bai, Hua

BACKGROUNDAcute myeloid leukemia (AML) is an immunosuppressive hematologic malignancy with a poor prognosis. An immunosuppressive microenvironment blunts AML therapy. However, the prognostic and therapeutic roles of the factors that mediate immunosuppression in AML remain elusive.METHODSS100 calcium-binding protein A4 (S100A4) was identified as an immunosuppression-mediating factor by analyzing The Cancer Genome Atlas AML project (TCGA-LAML) transcriptome data and data from AML-bearing mice and AML patients. The S100A4-mediated signaling pathway in myeloid-derived suppressor cells (MDSCs) was evaluated.RESULTSElevated S100A4 expression was positively associated with worse survival of AML patients, MDSCs, macrophages and immune checkpoints. S100A4 silencing downregulated the expression levels of MDSC-associated CD14, CCR2 and CCL2, reduced MDSC expansion and impaired MDSC-mediated inhibition of T cell activation and proliferation. S100A4-based prognostic signature (SPS) was an independent risk factor for AML patients. The high-risk group based on SPS was not only associated with adverse survival, MDSCs and macrophages and immune checkpoints but also insensitive to 25 chemotherapy drugs. It was also found that CCAAT enhancer binding protein beta (CEBPB) mediated S100A4 transcription. CEBPB silencing downregulated the expression levels of MDSC-associated CD14, CCR2 and CCL2. Mechanistically, S100A4 activated GP130/JAK2/STAT3 signaling in MDSCs by interacting with the cytokine-binding domain of GP130. Moreover, S100A4 mediated MDSC expansion through JAK2/STAT3 signaling.CONCLUSIONThis study uncovers the critical role of S100A4 in MDSC accumulation, and S100A4-based prognostic signature may guide chemotherapy sensitivity in patients with AML.

31 Dec 2024·Emerging Microbes & Infections

Immunocompetent mouse models revealed that S100A4 ⁺ monocytes/macrophages facilitate long-term Zika virus infection in the testes

Article

Author: Wang, Pei-Gang ; Gao, Na ; An, Jing ; Zhang, Chen ; Fan, Dong-Ying ; Chang, Jia-Tong ; Liu, Li-Bo ; Bian, Zhan-Zhan ; Yang, Wei

During its global epidemic, Zika virus (ZIKV) attracted widespread attention due to its link with various severe neurological symptoms and potential harm to male fertility. However, the understanding of how ZIKV invades and persists in the male reproductive system is limited due to the lack of immunocompetent small animal models. In this study, immunocompetent murine models were generated by using anti-IFNAR antibody blocked C57BL/6 male mice and human STAT2 (hSTAT2) knock in (KI) male mice. After infection, viral RNA could persist in the testes even after the disappearance of viremia. We also found a population of ZIKV-susceptible S100A4⁺ monocytes/macrophages that were recruited into testes from peripheral blood and played a crucial role for ZIKV infection in the testis. By using single-cell RNA sequencing, we also proved that S100A4⁺ monocytes/macrophages had a great impact on the microenvironment of ZIKV-infected testes, thus promoting ZIKV-induced testicular lesions. In conclusion, this study proposed a novel mechanism of long-term ZIKV infection in the male reproductive system.

01 Dec 2024·International Immunopharmacology

S100A4 promotes experimental autoimmune encephalomyelitis by impacting microglial inflammation through TLR4/NF-κB signaling pathway

Article

Author: Jingjing, He ; Jing, Li ; Shirong, Yan ; Lan, Ma ; Haijian, Yan ; Tongqian, Wu ; Fang, Yu ; Shihui, Mo

Multiple sclerosis (MS) is a neurodegenerating autoimmune disease with no clinical cure currently. The calcium-binding protein S100A4 has been demonstrated to exert regulatory roles in inflammatory disorders including MS. However, the precise mechanisms by which S100A4 regulates neuroinflammation in MS remains unknown. To investigate the regulatory effect of S100A4 on microglial inflammation and its impact on neuroinflammation, the mouse-derived microglia cell line BV2 cells were infected with lentivirus to knockout S100A4 for in vitro studies. Wild-type (WT) and S100A4^-/- mice were induced to develop experimental autoimmune encephalomyelitis (EAE), an animal model of MS, for in vivo investigation. Results indicated that the frequencies of microglia in the spinal cord and brain and the expression of S100A4 in these tissues varied kinetically along with the progression of the disease in mice with EAE. S100A4^-/- mice presented ameliorated clinical scores of EAE and exhibited less severe EAE signs, including inflammatory cell infiltration in the spinal cord and brain and demyelination of the spinal cord. Moreover, these mice demonstrated overall reduced levels of inflammatory cytokines in the spinal cord and brain. Compromised systematic inflammatory responses including circulating cytokines and frequencies of immune cells in the spleen were also observed in these mice. In addition, both exogenous and endogenous S100A4 could promote the microglial inflammation, affect the polarization of microglia and enhance inflamed microglia-mediated apoptosis of neuronal cells through TLR4/NF-κB signaling pathway. Thus, S100A4 may participate in the regulation of neuroinflammation at least partly through regulating the inflammation of microglia.

News (Medical) associated with S100A4

23 Oct 2024

·pipelinereview.com

Calluna Pharma Successfully Completes Phase 1 Clinical Study of CAL101, a First-in-Class Therapeutic for Fibrotic and Fibro-Inflammatory Indications

OSLO, Norway I October 23, 2024 I Calluna Pharma AS (Calluna), a clinical stage biotechnology company pioneering first-in-class antibodies to treat inflammatory and fibrotic diseases, today announced the completion of Phase 1 clinical study for CAL101, Calluna’s lead product candidate. The study demonstrated a favorable safety, pharmacokinetic (PK) and immunogenicity profile for the mAb. CAL101 is a first-in-class mAb that targets S100A4, a damage-associated molecular pattern (DAMP) protein implicated in serious and life-threatening diseases, such as idiopathic pulmonary fibrosis and systemic sclerosis. Preclinical studies have demonstrated the ability of CAL101 to prevent and treat fibrosis and modify the disease-specific activation of fibroblasts – the key effector cells driving progression of fibrosis 1 . Jonas Hallén M.D., Ph.D., Co-Founder and Chief Medical Officer of Calluna Pharma, commented: “We are encouraged by the findings from the Phase 1 study. These results are an important step forward in the development of our lead asset, CAL101, particularly for fibrotic and fibro-inflammatory diseases where there remains a critical need for innovative therapeutic options. We are excited as we now move into the next phase of clinical development.” The first-in-human, randomized, double-blind, placebo-controlled Phase 1 study in 57 subjects was designed to evaluate safety, tolerability, immunogenicity and PK, and was led by Professor Dave Singh at the Medicines Evaluation Unit in Manchester, UK 2 . The study tested single ascending doses of CAL101 in healthy volunteers and multiple ascending doses in patients with mild to moderate chronic plaque psoriasis. Summary of key CAL101 Phase 1 study results: In early 2025, Calluna plans to advance CAL101 into Phase 2 studies in fibrotic and fibro-inflammatory indications. For more information about Calluna Pharma, please visit: www.callunapharma.com SOURCE: Calluna Pharma

Phase 1

27 Jun 2024

·www.sciencedaily.com

Intriguing new tool for tendon healing: nanoparticles for precision drug delivery

Harnessing nanoparticles to deliver drugs precisely to a surgically repaired tendon is a promising new approach that reduced scar tissue formation and improved mechanical function. Harnessing nanoparticles to deliver drugs precisely to a surgically repaired tendon is a promising new approach that reduced scar tissue formation and improved mechanical function in a study appearing in Science Advances. Researchers' success in pinpointing a drug therapy inside the body, at the cellular level, proved to be a highly efficient delivery method that could be used to treat other injuries. Whether it's a season-ending Achilles rupture by pro footballer Aaron Rodgers or an everyday workplace accident, tendon injuries are common and can be life-changing. They require 300,000 surgeries per year and often result in lost work time and permanent impaired physical function. Typically, traumatic tendon injuries are surgically repaired with sutures, but optimal healing is often impaired by the tendon's propensity to heal with scar tissue that restricts tendon movement and function. Researchers at the University of Rochester and University of Oregon combined their expertise in tendon cell biology and drug delivery systems to find a better way to deliver therapies that can reduce scar tissue and facilitate improved healing. "There are very few effective drug regimens to assist the tendon healing process, despite the high number of these injuries and the poor outcomes that often result," said Alayna Loiselle, PhD, associate professor at the University of Rochester's Center for Musculoskeletal Research. "Systemic drug treatments delivered orally or via injection show poor tendon homing; in some cases, less than 1 percent of a systemically delivered medication reaches the healing tendon. Local administration of drugs directly to the tendon has disadvantages as well, including potential tissue damage from the injection and poor control over drug concentrations at the point of injury." "We want to pivot from using suturing alone to incorporating therapeutics," said Emmanuela Adjei-Sowah, a Biomedical Engineering PhD student at the University of Rochester, who has spent the past several years working with co-authors Loiselle, Danielle S.W. Benoit, PhD, and others to develop the nanoparticle delivery system to improve healing in tendon injuries. "Advances in multiomics and drug delivery using nanoparticles open up new possibilities in treatment." The challenge for researchers was to identify which substances could assist tendon healing. Molecular 'map' of healing process charts a new therapeutic path "The fundamental cellular and molecular mechanisms that drive scar-mediated tendon healing are really only just beginning to be well-defined," Loiselle said. "Our prior work used spatial transcriptomic profiling to define a molecular map of the healing tendon. In subsequent analysis of this data, we found that the area right at the injury site had high levels of Acp5 gene expression, which was both surprising and exciting." The Acp5 gene produces a protein called Tartrate Resistant Acid Phosphatase (TRAP); both are known to occur as injured bones recover and rebuild. High TRAP activity within the healing tendon allowed researchers to employ a peptide that binds with TRAP to deliver medication directly to the healing tendon site. "While Benoit's lab has previously used TRAP-binding peptide nanoparticles (TBP-NP) for targeted drug delivery to bone, high TRAP activity in the healing tendon opened up an entirely new research direction," Loiselle said. Prior to initiating studies with therapeutic agents, the team completed a series of dose and timing studies, using a mouse model of complete transection and surgical repair of the flexor tendon, to define the window in which their drug delivery system could most effectively target the healing tendon. "Defining an optimal treatment window is critical to successfully developing an innovative and effective drug delivery system that improves tendon healing by encouraging a more regenerative, rather than fibrotic, healing cascade," said Benoit, the Lorry Lokey Department Chair and Professor in the Department of Bioengineering at the University of Oregon. "In addition, by defining the optimal therapeutic window for this drug delivery system, we can mitigate the unwanted side effects that typically accompany the high doses or multiple doses required to achieve sufficient drug accumulation in the tissue." As a therapeutic, the team chose Niclosamide, which inhibits S100a4, a protein that Loiselle's lab already identified as contributing to scar formation. Previous work from Loiselle's lab demonstrated that genetic knockdown of S100a4 improved mechanical and functional outcomes in this mouse tendon healing model. S100a4 has been implicated in scar formation in many tissues, including the liver, heart, lung, and oral submucosa; Loiselle's discovery that it complicates tendon healing gave them a therapeutic target for this study, where they used their TRAP-binding peptide nanoparticle drug delivery system to precisely affect the injured tendon. As a comparison, they delivered Niclosamide systemically; it did slightly reduce the amount of S100a4 in the healing tendon but it had no beneficial impact on the healing process. In contrast, delivery of the same dose of Niclosamide using the nanoparticle system resulted in robust inhibition of S100a4 mRNA and protein levels in the healing tendon. This targeted drug delivery method also significantly benefited the tendon healing process. TBP-NP delivery of Niclosamide improved both functional range of motion recovery and increased the mechanical integrity of the healing tendon across both short- and longer-term timepoints. Importantly, these sustained effects occurred with just a single treatment. Researchers will continue their work to define how broadly the system can be used for other tendon injuries and disease, as well as other types of tissue injury that result in scar formation. "The beauty of this system is that it can be loaded with different kinds of drugs to target different molecular processes or pathways," said Adjei-Sowah.

23 Jan 2024

·www.pharmaceutical-technology.com

Newly launched Calluna raises $81m to advance monoclonal antibody pipeline

Calluna will use the funding to develop four immunotherapy candidates. Credit: Maria Dryfhout via Shutterstock. European biotechs Oxitope Pharma and Arxx Therapeutics have merged to form Calluna Pharma, raising €75m ($81m) in a Series A funding round. Free Report How is the Biopharmaceutical industry evolving? 2021 was a year of continued innovation and change in the Biopharmaceutical industry. As the COVID-19 pandemic continues to take its toll on businesses worldwide, it’s time to look for new ways to create value, prepare for the future, and remain competitive in the ever-changing landscape. GlobalData’s expansive report examines the business environment and trends that shape the Biopharmaceutical industry. We highlight the most impactful emerging technologies, as well as the industry, regulatory, and macroeconomic factors that influence growth prospects. Access the report to: Benchmark the impact of major themes on the Biopharmaceutical industry. Gain a deeper "on the ground" perspective through exclusive opinions and analysis from industry respondents. Evaluate the effects of COVID-19 on the sector. Download the full report to understand what to expect and how to align your strategies for success. 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Our services are intended for corporate subscribers and you warrant that the email address submitted is your corporate email address. Thank you. You will recieve your mail in sometime.So, please check your email to download the Report. Go deeper with GlobalData Reports LOA and PTSR Model - Monoclonal Antibody Conjugate 3 To Target Egfr For Oncology in Malignant Mes... Reports LOA and PTSR Model - Monoclonal Antibody Conjugate 3 To Target Egfr For Oncology in Non-Small Cel... Premium Insights The gold standard of business intelligence. Find out more Related Company Profiles Boehringer Ingelheim International GmbH GSK plc View all Led by existing lead investors Forbion, Sarsia, p53, and Investinor, the funding from the round will go towards a pipeline of monoclonal antibodies targeting immunological diseases. Calluna’s lead candidate CAL101 is a monoclonal antibody (mAb) designed to neutralise S100A4, a damage-associated molecular pattern (DAMP) protein. When released in excess or at the wrong time, DAMPs can contribute to the development and progression of diseases involving inflammation and tissue damage such as rheumatoid arthritis, steroid-insensitive asthma, chronic kidney disease, and idiopathic pulmonary fibrosis. CAL102, a monoclonal antibody that neutralises oxidised phospholipids, is another therapy in development by Calluna. It acts by disrupting the underlying pathways associated with conditions characterised by inflammation and fibrosis. The company has two other candidates, CAL103 and CAL104, which are both in the discovery phase. Netherlands-based Oxitope launched in 2020, a few years after Norway-based Arxx in 2018, with both startups focusing energy on therapeutic antibodies. It’s already been a big year for immunotherapies. Earlier this month, pharma giant Boehringer Ingelheim teamed up with 3T Biosciences in a deal totalling $538.5m to advance cancer immunotherapies, using 3T’s T-Cell Receptor Antigen and Cross-Reactivity Engine (TRACE) discovery platform to discover and develop the immunotherapies. This development comes after GSK purchased Aiolos Bio in a large $1.4bn acquisition , granting GSK access to Aiolos’ monoclonal antibody AIO-001. The candidate, soon to be investigated in a Phase II study, targets a cytokine thought to play a role in asthma and other inflammation diseases. In the announcement accompanying the funding round, Calluna chief executive officer John Montana said: “In joining forces, these two key players in the innate immunology space have created an exciting new clinical company that has four promising therapies in its pipeline with excellent preclinical proof-of-concept data.” Free Report How is the Biopharmaceutical industry evolving? 2021 was a year of continued innovation and change in the Biopharmaceutical industry. As the COVID-19 pandemic continues to take its toll on businesses worldwide, it’s time to look for new ways to create value, prepare for the future, and remain competitive in the ever-changing landscape. GlobalData’s expansive report examines the business environment and trends that shape the Biopharmaceutical industry. We highlight the most impactful emerging technologies, as well as the industry, regulatory, and macroeconomic factors that influence growth prospects. Access the report to: Benchmark the impact of major themes on the Biopharmaceutical industry. Gain a deeper "on the ground" perspective through exclusive opinions and analysis from industry respondents. Evaluate the effects of COVID-19 on the sector. Download the full report to understand what to expect and how to align your strategies for success. By GlobalData Submit Country Code * UK (+44) USA (+1) Algeria (+213) Andorra (+376) Angola (+244) Anguilla (+1264) Antigua & Barbuda (+1268) Argentina (+54) Armenia (+374) Aruba (+297) Australia (+61) Austria (+43) Azerbaijan (+994) Bahamas (+1242) Bahrain (+973) Bangladesh (+880) Barbados (+1246) Belarus (+375) Belgium (+32) Belize (+501) Benin (+229) Bermuda (+1441) Bhutan (+975) Bolivia (+591) Bosnia Herzegovina (+387) Botswana (+267) Brazil (+55) Brunei (+673) Bulgaria (+359) Burkina Faso (+226) Burundi (+257) Cambodia (+855) Cameroon (+237) Canada (+1) Cape Verde Islands (+238) Cayman Islands (+1345) Central African Republic (+236) Chile (+56) China (+86) Colombia (+57) Comoros (+269) Congo (+242) Cook Islands (+682) Costa Rica (+506) Croatia (+385) Cuba (+53) Cyprus North (+90392) Cyprus South (+357) Czech Republic (+42) Denmark (+45) Djibouti (+253) Dominica (+1809) Dominican Republic (+1809) Ecuador (+593) Egypt (+20) El Salvador (+503) Equatorial Guinea (+240) Eritrea (+291) Estonia (+372) Ethiopia (+251) Falkland Islands (+500) Faroe Islands (+298) Fiji (+679) Finland (+358) France (+33) French Guiana (+594) French Polynesia (+689) Gabon (+241) Gambia (+220) Georgia (+7880) Germany (+49) Ghana (+233) Gibraltar (+350) Greece (+30) Greenland (+299) Grenada (+1473) Guadeloupe (+590) Guam (+671) Guatemala (+502) Guinea (+224) Guinea - Bissau (+245) Guyana (+592) Haiti (+509) Honduras (+504) Hong Kong (+852) Hungary (+36) Iceland (+354) India (+91) Indonesia (+62) Iran (+98) Iraq (+964) Ireland (+353) Israel (+972) Italy (+39) Jamaica (+1876) Japan (+81) Jordan (+962) Kazakhstan (+7) Kenya (+254) Kiribati (+686) Korea North (+850) Korea South (+82) Kuwait (+965) Kyrgyzstan (+996) Laos (+856) Latvia (+371) Lebanon (+961) Lesotho (+266) Liberia (+231) Libya (+218) Liechtenstein (+417) Lithuania (+370) Luxembourg (+352) Macao (+853) Macedonia (+389) Madagascar (+261) Malawi (+265) Malaysia (+60) Maldives (+960) Mali (+223) Malta (+356) Marshall Islands (+692) Martinique (+596) Mauritania (+222) Mayotte (+269) Mexico (+52) Micronesia (+691) Moldova (+373) Monaco (+377) Mongolia (+976) Montserrat (+1664) Morocco (+212) Mozambique (+258) Myanmar (+95) Namibia (+264) Nauru (+674) Nepal (+977) Netherlands (+31) New Caledonia (+687) New Zealand (+64) Nicaragua (+505) Niger (+227) Nigeria (+234) Niue (+683) Norfolk Islands (+672) Northern Marianas (+670) Norway (+47) Oman (+968) Palau (+680) Panama (+507) Papua New Guinea (+675) Paraguay (+595) Peru (+51) Philippines (+63) Poland (+48) Portugal (+351) Puerto Rico (+1787) Qatar (+974) Reunion (+262) Romania (+40) Russia (+7) Rwanda (+250) San Marino (+378) Sao Tome & Principe (+239) Saudi Arabia (+966) Senegal (+221) Serbia (+381) Seychelles (+248) Sierra Leone (+232) Singapore (+65) Slovak Republic (+421) Slovenia (+386) Solomon Islands (+677) Somalia (+252) South Africa (+27) Spain (+34) Sri Lanka (+94) St. Helena (+290) St. Kitts (+1869) St. Lucia (+1758) Sudan (+249) Suriname (+597) Swaziland (+268) Sweden (+46) Switzerland (+41) Syria (+963) Taiwan (+886) Tajikstan (+7) Thailand (+66) Togo (+228) Tonga (+676) Trinidad & Tobago (+1868) Tunisia (+216) Turkey (+90) Turkmenistan (+7) Turkmenistan (+993) Turks & Caicos Islands (+1649) Tuvalu (+688) Uganda (+256) Ukraine (+380) United Arab Emirates (+971) Uruguay (+598) Uzbekistan (+7) Vanuatu (+678) Vatican City (+379) Venezuela (+58) Vietnam (+84) Virgin Islands - British (+1284) Virgin Islands - US (+1340) Wallis & Futuna (+681) Yemen (North)(+969) Yemen (South)(+967) Zambia (+260) Zimbabwe (+263) Country * UK USA Afghanistan Åland Islands Albania Algeria American Samoa Andorra Angola Anguilla Antarctica Antigua and Barbuda Argentina Armenia Aruba Australia Austria Azerbaijan Bahamas Bahrain Bangladesh Barbados Belarus Belgium Belize Benin Bermuda Bhutan Bolivia Bonaire, Sint Eustatius and Saba Bosnia and Herzegovina Botswana Bouvet Island Brazil British Indian Ocean Territory Brunei Darussalam Bulgaria Burkina Faso Burundi Cambodia Cameroon Canada Cape Verde Cayman Islands Central African Republic Chad Chile China Christmas Island Cocos Islands Colombia Comoros Congo Democratic Republic of the Congo Cook Islands Costa Rica Côte d"Ivoire Croatia Cuba Curaçao Cyprus Czech Republic Denmark Djibouti Dominica Dominican Republic Ecuador Egypt El Salvador Equatorial Guinea Eritrea Estonia Ethiopia Falkland Islands Faroe Islands Fiji Finland France French Guiana French Polynesia French Southern Territories Gabon Gambia Georgia Germany Ghana Gibraltar Greece Greenland Grenada Guadeloupe Guam Guatemala Guernsey Guinea Guinea-Bissau Guyana Haiti Heard Island and McDonald Islands Holy See Honduras Hong Kong Hungary Iceland India Indonesia Iran Iraq Ireland Isle of Man Israel Italy Jamaica Japan Jersey Jordan Kazakhstan Kenya Kiribati North Korea South Korea Kuwait Kyrgyzstan Lao Latvia Lebanon Lesotho Liberia Libyan Arab Jamahiriya Liechtenstein Lithuania Luxembourg Macao Macedonia, The Former Yugoslav Republic of Madagascar Malawi Malaysia Maldives Mali Malta Marshall Islands Martinique Mauritania Mauritius Mayotte Mexico Micronesia Moldova Monaco Mongolia Montenegro Montserrat Morocco Mozambique Myanmar Namibia Nauru Nepal Netherlands New Caledonia New Zealand Nicaragua Niger Nigeria Niue Norfolk Island Northern Mariana Islands Norway Oman Pakistan Palau Palestinian Territory Panama Papua New Guinea Paraguay Peru Philippines Pitcairn Poland Portugal Puerto Rico Qatar Réunion Romania Russian Federation Rwanda Saint Helena, Ascension and Tristan da Cunha Saint Kitts and Nevis Saint Lucia Saint Pierre and Miquelon Saint Vincent and The Grenadines Samoa San Marino Sao Tome and Principe Saudi Arabia Senegal Serbia Seychelles Sierra Leone Singapore Slovakia Slovenia Solomon Islands Somalia South Africa South Georgia and The South Sandwich Islands Spain Sri Lanka Sudan Suriname Svalbard and Jan Mayen Swaziland Sweden Switzerland Syrian Arab Republic Taiwan Tajikistan Tanzania Thailand Timor-Leste Togo Tokelau Tonga Trinidad and Tobago Tunisia Turkey Turkmenistan Turks and Caicos Islands Tuvalu Uganda Ukraine United Arab Emirates US Minor Outlying Islands Uruguay Uzbekistan Vanuatu Venezuela Vietnam British Virgin Islands US Virgin Islands Wallis and Futuna Western Sahara Yemen Zambia Zimbabwe Kosovo By downloading this case study, you acknowledge that GlobalData may share your information with GlobalData and that your personal data will be used as described in their Privacy Policy Submit Visit our Privacy Policy for more information about our services, how GlobalData may use, process and share your personal data, including information on your rights in respect of your personal data and how you can unsubscribe from future marketing communications. 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