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Janice M. Reichert 《MABS-AUSTIN》2012,4(3):413-415
Therapeutic monoclonal antibodies (mAbs) are currently being approved for marketing in Europe and the United States, as well as other countries, on a regular basis. As more mAbs become available to physicians and patients, keeping track of the number, types, production cell lines, antigenic targets, and dates and locations of approvals has become challenging. Data are presented here for 34 mAbs that were approved in either Europe or the United States (US) as of March 2012, and nimotuzumab, which is marketed outside Europe and the US. Of the 34 mAbs, 28 (abciximab, rituximab, basiliximab, palivizumab, infliximab, trastuzumab, alemtuzumab, adalimumab, tositumomab-I131, cetuximab, ibrituximab tiuxetan, omalizumab, bevacizumab, natalizumab, ranibizumab, panitumumab, eculizumab, certolizumab pegol, golimumab, canakinumab, catumaxomab, ustekinumab, tocilizumab, ofatumumab, denosumab, belimumab, ipilimumab, brentuximab) are currently marketed in Europe or the US. Data for six therapeutic mAbs (muromonab-CD3, nebacumab, edrecolomab, daclizumab, gemtuzumab ozogamicin, efalizumab) that were approved but have been withdrawn or discontinued from marketing in Europe or the US are also included.Of the 28 mAbs currently marketed in the European Union or the US, 26 are marketed in Europe and 27 are marketed in the US, with 25 marketed in both regions (1 Of the 28 mAbs that are marketed in one or the other region, 43% (12/28) are produced in Chinese hamster ovary (CHO) cells, 25% (7/28) are produced in SP2/0 cells,2 18% (5/28) are produced in NS0 cells,3 and 7% (2/28) are produced in hybridomas. The remaining two products (ranibizumab, certolizumab pegol) are antigen-binding fragments (Fab) that are produced in E. coli. Humanized and human mAbs comprise 36% (10/28) and 32% (9/28) of the total, respectively, while 21% (6/28) are chimeric and 11% (3/28) are murine. Most (75%; 21/28) are canonical full-length mAbs. Of the 7 non-canonical mAbs, three (abciximab, ranibizumab, certolizumab pegol) are Fab, with one of these (certolizumab pegol) pegylated; two (tositumomab-I131, ibrituximab tiuxetan) are radiolabeled when administered to patients; one (brentuximab vedotin) is an antibody-drug conjugate (ADC); and one is bispecific (catumaxomab). Although 16 marketed mAbs target unique antigens, CD20 and tumor necrosis factor are each targeted by 4 mAbs, and epidermal growth factor receptor (EGFR) and vascular endothelial growth factor are each targeted by 2 mAbs. If approved, pertuzumab, which is undergoing regulatory review in Europe and the US as a treatment for breast cancer, would be one of 2 mAbs that target human epidermal growth factor receptor 2 on the market.Table 1. Therapeutic monoclonal antibodies marketed or in review in the European Union or United States
Open in a separate window*As of March 10, 2012. #Country-specific approval; approved under concertation procedure **Product manufactured for Phase 1 study in humans. Abbreviations: BLyS, B lymphocyte stimulator; C5, complement 5; CD, cluster of differentiation; CHO, Chinese hamster ovary; CTLA-4, cytotoxic T lymphocyte antigen 4; EGFR, epidermal growth factor receptor; EpCAM, epithelial cell adhesion molecule; Fab, antigen-binding fragment; GP glycoprotein; IL, interleukin; NA, not approved; PA, protective antigen; RANK-L, receptor activator of NFκb ligand; RSV, respiratory syncytial virus; TNF, tumor necrosis factor; VEGF, vascular endothelial growth factor. Sources: European Medicines Agency public assessment reports, United States Food and Drug Administration (drugs@fda), the international ImMunoGeneTics information system® (www.imgt.org/mAb-DB/index).In addition to the 28 mAbs currently marketed, six mAbs were approved in at least one country of Europe or in the US, but were subsequently withdrawn or discontinued from marketing for various reasons (4,5 Nebacumab (Centoxin®), a human IgM, was approved in The Netherlands, Britain, Germany and France during 1991 as a treatment for Gram-negative sepsis,6 but the product was subsequently withdrawn for safety, efficacy and commercial reasons.7 The murine anti-epithelial cell adhesion molecule (EpCAM) edrecolomab (Panorex®) was approved in Germany in 1995 as an adjuvant treatment for colon cancer, but subsequently withdrawn because of the product’s lack of efficacy.8 Daclizumab was first approved in 1997 for prophylaxis of acute organ rejection in patients receiving renal transplants, but the product was voluntarily withdrawn from the market in Europe effective January 1, 20099 and discontinued for the US market because of the availability of alternative therapy and the diminished market demand.10 The first ADC to be approved, gemtuzumab ozogamicin was marketed in the US for a decade before being voluntarily withdrawn in 2010. The product was approved under the accelerated approval mechanism as a treatment for acute myeloid leukemia (AML), but was withdrawn when a confirmatory clinical trial and post-approval use did not show evidence of clinical benefit in AML patients.11 Efalizumab (Raptiva®) was approved in the US and Europe in 2003 and 2004, respectively, as a treatment for adults with moderate to severe plaque psoriasis, but the product was voluntarily withdrawn from both markets in 2009 because of the risk of side effects, including progressive multifocal leukoencephalopathy.12,13Table 2. Therapeutic monoclonal antibodies withdrawn or discontinued from marketing in the European Union or United States
Open in a separate windowNote: Information current as of March 10, 2012. *European country-specific approval. Abbreviations: CD, cluster of differentiation; CHO, Chinese hamster ovary; EpCAM, epithelial cell adhesion molecule; IL, interleukin; NA, not approved. Sources: European Medicines Agency public assessment reports, United States Food and Drug Administration (drugs@fda), the international ImMunoGeneTics information system® (www.imgt.org/mAb-DB/index).The European Union and the US are not necessarily the first or only markets for therapeutic mAbs (14 Mogamulizumab is a defucosylated humanized anti-CC chemokine receptor 4 (CCR4) antibody developed by Kyowa Hakko Kirin Co Ltd.15 The mAb is undergoing regulatory review in Japan as a treatment for adult T-cell leukemia-lymphoma and peripheral T-cell lymphoma.Table 3. Therapeutic monoclonal antibodies marketed or in review outside the European Union or United States
Open in a separate windowNote: Information current as of March 10, 2012. Abbreviations: CCR, chemokine receptor; EGFR, epidermal growth factor receptor.The 35 marketed mAbs, most of which are canonical full-length IgG1, paved the way for the next generation of antibody-based therapeutics such as ADCs, bispecific antibodies, engineered antibodies, and antibody fragments or domains. The commercial pipeline includes ~350 mAbs now being evaluated in clinical studies around the world as treatments for many indications, including cancer, immunological disorders and infectious diseases.16 The compendium of marketed therapeutic antibodies may thus be substantially larger in the future. 相似文献
International non-proprietary name (Trade name) | Manufacturing cell line | Type | Target | First EU (US) approval year |
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Abciximab (Reopro®) | Sp2/0 | Chimeric IgG1κ Fab | GPIIb/IIIa | 1995# (1994) |
Rituximab (MabThera®, Rituxan®) | CHO | Chimeric IgG1κ | CD20 | 1998 (1997) |
Basiliximab (Simulect®) | Sp2/0 | Chimeric IgG1κ | IL2R | 1998 (1998) |
Palivizumab (Synagis®) | NS0 | Humanized IgG1κ | RSV | 1999 (1998) |
Infliximab (Remicade®) | Sp2/0 | Chimeric IgG1κ | TNF | 1999 (1998) |
Trastuzumab (Herceptin®) | CHO | Humanized IgG1κ | HER2 | 2000 (1998) |
Alemtuzumab (MabCampath, Campath-1H®) | CHO | Humanized IgG1κ | CD52 | 2001 (2001) |
Adalimumab (Humira®) | CHO | Human IgG1κ | TNF | 2003 (2002) |
Tositumomab-I131 (Bexxar®) | Hybridoma | Murine IgG2aλ | CD20 | NA (2003) |
Cetuximab (Erbitux®) | Sp2/0 | Chimeric IgG1κ | EGFR | 2004 (2004) |
Ibritumomab tiuxetan (Zevalin®) | CHO | Murine IgG1κ | CD20 | 2004 (2002) |
Omalizumab (Xolair®) | CHO | Humanized IgG1κ | IgE | 2005 (2003) |
Bevacizumab (Avastin®) | CHO | Humanized IgG1κ | VEGF | 2005 (2004) |
Natalizumab (Tysabri®) | NS0 | Humanized IgG4κ | α4-integrin | 2006 (2004) |
Ranibizumab (Lucentis®) | E. coli | Humanized IgG1κ Fab | VEGF | 2007 (2006) |
Panitumumab (Vectibix®) | CHO | Human IgG2κ | EGFR | 2007 (2006) |
Eculizumab (Soliris®) | NS0 | Humanized IgG2/4κ | C5 | 2007 (2007) |
Certolizumab pegol (Cimzia®) | E. coli | Humanized IgG1κ Fab, pegylated | TNF | 2009 (2008) |
Golimumab (Simponi®) | Sp2/0 | Human IgG1κ | TNF | 2009 (2009) |
Canakinumab (Ilaris®) | Sp2/0 | Human IgG1κ | IL1b | 2009 (2009) |
Catumaxomab (Removab®) | Hybrid hybridoma | Rat IgG2b/mouse IgG2a bispecific | EpCAM/CD3 | 2009 (NA) |
Ustekinumab (Stelara®) | Sp2/0 | Human IgG1κ | IL12/23 | 2009 (2009) |
Tocilizumab (RoActemra, Actemra®) | CHO | Humanized IgG1κ | IL6R | 2009 (2010) |
Ofatumumab (Arzerra®) | NS0 | Human IgG1κ | CD20 | 2010 (2009) |
Denosumab (Prolia®) | CHO | Human IgG2λ | RANK-L | 2010 (2010) |
Belimumab (Benlysta®) | NS0 | Human IgG1κ | BLyS | 2011 (2011) |
Raxibacumab (Pending) | NS0** | Human IgG1κ | B. anthrasis PA | NA (In review) |
Ipilimumab (Yervoy®) | CHO | Human IgG1κ | CTLA-4 | 2011 (2011) |
Brentuximab vedotin (Adcentris®) | CHO | Chimeric IgG1κ; conjugated to monomethyl auristatin E | CD30 | In review (2011) |
Pertuzumab (Pending) | CHO | Humanized IgG1κ | HER2 | In review (in review) |
International proprietary name (Trade name) | Manufacturing cell line | Type | Target | First EU (US) approval year |
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Muromonab-CD3 (Orthoclone OKT3®) | Hybridoma | Murine IgG2a | CD3 | 1986* (1986) |
Nebacumab (Centoxin®) | Hybridoma | Human IgM | Endotoxin | 1991*(NA) |
Edrecolomab (Panorex®) | Hybridoma | Murine IgG2a | EpCAM | 1995*(NA) |
Daclizumab (Zenapax®) | NS0 | Humanized IgG1κ | IL2R | 1999 (1997) |
Gemtuzumab ozogamicin (Mylotarg®) | NS0 | Humanized IgG4κ | CD33 | NA (2000) |
Efalizumab (Raptiva®) | CHO | Humanized IgG1κ | CD11a | 2004 (2003) |
International proprietary name (Trade name) | Manufacturing cell line | Type | Target | First approval year |
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Nimotuzumab (TheraCIM®, BIOMAB-EGFR®) | NS0 | Humanized IgG1κ | EGFR | 1999 |
Mogamulizumab | [Not found] | Humanized IgG1κ | CCR4 | In review in Japan |
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Pavan Umate 《Plant signaling & behavior》2011,6(3):335-338
The enzymes called lipoxygenases (LOXs) can dioxygenate unsaturated fatty acids, which leads to lipoperoxidation of biological membranes. This process causes synthesis of signaling molecules and also leads to changes in cellular metabolism. LOXs are known to be involved in apoptotic (programmed cell death) pathway, and biotic and abiotic stress responses in plants. Here, the members of LOX gene family in Arabidopsis and rice are identified. The Arabidopsis and rice genomes encode 6 and 14 LOX proteins, respectively, and interestingly, with more LOX genes in rice. The rice LOXs are validated based on protein alignment studies. This is the first report wherein LOXs are identified in rice which may allow better understanding the initiation, progression and effects of apoptosis, and responses to bitoic and abiotic stresses and signaling cascades in plants.Key words: apoptosis, biotic and abiotic stresses, genomics, jasmonic acid, lipidsLipoxygenases (linoleate:oxygen oxidoreductase, EC 1.13.11.-; LOXs) catalyze the conversion of polyunsaturated fatty acids (lipids) into conjugated hydroperoxides. This process is called hydroperoxidation of lipids. LOXs are monomeric, non-heme and non-sulfur, but iron-containing dioxygenases widely expressed in fungi, animal and plant cells, and are known to be absent in prokaryotes. However, a recent finding suggests the existence of LOX-related genomic sequences in bacteria but not in archaea.1 The inflammatory conditions in mammals like bronchial asthama, psoriasis and arthritis are a result of LOXs reactions.2 Further, several clinical conditions like HIV-1 infection,3 disease of kidneys due to the activation of 5-lipoxygenase,4,5 aging of the brain due to neuronal 5-lipoxygenase6 and atherosclerosis7 are mediated by LOXs. In plants, LOXs are involved in response to biotic and abiotic stresses.8 They are involved in germination9 and also in traumatin and jasmonic acid biochemical pathways.10,11 Studies on LOX in rice are conducted to develop novel strategies against insect pests12 in response to wounding and insect attack,13 and on rice bran extracts as functional foods and dietary supplements for control of inflammation and joint health.14 In Arabidopsis, LOXs are studied in response to natural and stress-induced senescence,15 transition to flowering,16 regulation of lateral root development and defense response.17The arachidonic, linoleic and linolenic acids can act as substrates for different LOX isozymes. A hydroperoxy group is added at carbons 5, 12 or 15, when arachidonic acid is the substrate, and so the LOXs are designated as 5-, 12- or 15-lipoxygenases. Sequences are available in the database for plant lipoxygenases (EC:1.13.11.12), mammalian arachidonate 5-lipoxygenase (EC:1.13.11.34), mammalian arachidonate 12-lipoxygenase (EC:1.13.11.31) and mammalian erythroid cell-specific 15-lipoxygenase (EC:1.13.11.33). The prototype member for LOX family, LOX-1 of Glycine max L. (soybean) is a 15-lipoxygenase. The LOX isoforms of soybean (LOX-1, LOX-2, LOX-3a and LOX-3b) are the most characterized of plant LOXs.18 In addition, five vegetative LOXs (VLX-A, -B, -C, -D, -E) are detected in soybean leaves.19 The 3-dimensional structure of soybean LOX-1 has been determined.20,21 LOX-1 was shown to be made of two domains, the N-terminal domain-I which forms a β-barrel of 146 residues, and a C-terminal domain-II of bundle of helices of 693 residues21 (Fig. 1). The iron atom was shown to be at the centre of domain-II bound by four coordinating ligands, of which three are histidine residues.22Open in a separate windowFigure 1Three-dimensional structure of soybean lipoxygenase L-1. The domain I (N-terminal) and domain II (C-terminal) are indicated. The catalytic iron atom is embedded in domain II (PDB ID-1YGE).21This article describes identification of LOX genes in Arabidopsis and rice. The Arabidopsis genome encodes for six LOX proteins23 (www.arabidopsis.org) (Locus Annotation Nomenclature A* B* C* AT1G55020 lipoxygenase 1 (LOX1) LOX1 859 98044.4 5.2049 AT1G17420 lipoxygenase 3 (LOX3) LOX3 919 103725.1 8.0117 AT1G67560 lipoxygenase family protein LOX4 917 104514.6 8.0035 AT1G72520 lipoxygenase, putative LOX6 926 104813.1 7.5213 AT3G22400 lipoxygenase 5 (LOX5) LOX5 886 101058.8 6.6033 AT3G45140 lipoxygenase 2 (LOX2) LOX2 896 102044.7 5.3177