Editor’s CornEr
`mAbs 4:3, 413-415; May/June 2012; © 2012 Landes Bioscience
`
`Editor’s CornEr
`
`Marketed therapeutic antibodies compendium
`
`Janice M. reichert
`
`Landes Bioscience; Austin, tX UsA
`
`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`edrecolomab, daclizumab, gemtuzumab ozogamicin, efalizumab) that were approved but have been withdrawn or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 mar-
`keted in the US, with 25 marketed in
`both regions (Table 1). Catumaxomab
`is approved in Europe but not the US;
`tositumomab-I131 is marketed in the
`US but not Europe. Brentuximab vedo-
`tin was approved in the US in 2011 and,
`as of March 2012, a marketing applica-
`tion for the mAb is undergoing review
`by the European Medicines Agency.1 Of
`the 28 mAbs that are marketed in one or
`the other region, 43% (12/28) are pro-
`duced 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 prod-
`ucts (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, respec-
`tively, 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 (cer-
`tolizumab pegol) pegylated; two (tosi-
`tumomab-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 anti-
`gens, CD20 and tumor necrosis factor
`are each targeted by 4 mAbs, and epider-
`mal growth factor receptor (EGFR) and
`vascular endothelial growth factor are
`each targeted by 2 mAbs. If approved,
`pertuzumab, which is undergoing regu-
`latory 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.
`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 vari-
`ous reasons (Table 2). First approved in
`the US
`in 1986, muromonab-CD3
`(Orthoclone OKT3®) was a murine
`IgG2a used to treat acute kidney allograft
`rejection; however, manufacturing was
`discontinued in 2010 due to the availabil-
`ity of other treatments with similar effi-
`cacy and fewer side effects, and declining
`sales.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 mol-
`ecule (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 prophy-
`laxis of acute organ rejection in patients
`receiving renal transplants, but the prod-
`uct was voluntarily withdrawn from the
`market in Europe effective January 1,
`2009 9 and discontinued for the US mar-
`ket because of the availability of alterna-
`tive 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 vol-
`untarily withdrawn in 2010. The prod-
`uct 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 treat-
`ment for adults with moderate to severe
`plaque psoriasis, but the product was
`
`Correspondence to: Janice M. Reichert; Email: janice.reichert@landesbioscience.com
`Submitted: 03/07/12; Accepted: 03/07/12
`http://dx.doi.org/10.4161/mabs.19931
`
`www.landesbioscience.com
`
`mAbs
`
`413
`
`© 2 0 11 La n d e s B io s cie n ce .
`D o n o t d is trib u te .
`
`Genzyme Ex. 1039, pg 922
`
`

`

`Table 1. therapeutic monoclonal antibodies marketed or in review in the European Union or United states
`International non-proprietary name (Trade name) Manufacturing cell line
`Type
`Abciximab (reopro®)
`sp2/0
`Chimeric igG1κ Fab
`rituximab (Mabthera®, rituxan®)
`CHo
`Chimeric igG1κ
`Basiliximab (simulect®)
`sp2/0
`Chimeric igG1κ
`Palivizumab (synagis®)
`ns0
`Humanized igG1κ
`infliximab (remicade®)
`sp2/0
`Chimeric igG1κ
`trastuzumab (Herceptin®)
`CHo
`Humanized igG1κ
`Alemtuzumab (MabCampath, Campath-1H®)
`CHo
`Humanized igG1κ
`Adalimumab (Humira®)
`CHo
`Human igG1κ
`tositumomab-i131 (Bexxar®)
`Hybridoma
`Murine igG2aλ
`sp2/0
`Cetuximab (Erbitux®)
`Chimeric igG1κ
`ibritumomab tiuxetan (Zevalin®)
`CHo
`Murine igG1κ
`omalizumab (Xolair®)
`CHo
`Humanized igG1κ
`Bevacizumab (Avastin®)
`CHo
`Humanized igG1κ
`natalizumab (tysabri®)
`ns0
`Humanized igG4κ
`E. coli
`ranibizumab (Lucentis®)
`Humanized igG1κ Fab
`CHo
`Panitumumab (Vectibix®)
`Human igG2κ
`Eculizumab (soliris®)
`ns0
`Humanized igG2/4κ
`
`Certolizumab pegol (Cimzia®)
`
`Golimumab (simponi®)
`Canakinumab (ilaris®)
`
`E. coli
`
`sp2/0
`sp2/0
`
`Catumaxomab (removab®)
`
`Hybrid hybridoma
`
`Humanized igG1κ Fab,
`pegylated
`
`Human igG1κ
`Human igG1κ
`
`rat igG2b/mouse igG2a
`bispecific
`
`Target
`GPiib/iiia
`Cd20
`iL2r
`rsV
`tnF
`HEr2
`Cd52
`tnF
`Cd20
`EGFr
`Cd20
`igE
`VEGF
`α4-integrin
`VEGF
`EGFr
`C5
`
`tnF
`
`tnF
`iL1b
`
`First EU (US) approval year
`1995* (1994)
`1998 (1997)
`1998 (1998)
`1999 (1998)
`1999 (1998)
`2000 (1998)
`2001 (2001)
`2003 (2002)
`nA (2003)
`2004 (2004)
`2004 (2002)
`2005 (2003)
`2005 (2004)
`2006 (2004)
`2007 (2006)
`2007 (2006)
`2007 (2007)
`
`2009 (2008)
`
`2009 (2009)
`2009 (2009)
`
`EpCAM/Cd3
`
`2009 (nA)
`
`Ustekinumab (stelara®)
`tocilizumab (roActemra, Actemra®)
`ofatumumab (Arzerra®)
`denosumab (Prolia®)
`Belimumab (Benlysta®)
`raxibacumab (Pending)
`ipilimumab (Yervoy®)
`
`Brentuximab vedotin (Adcentris®)
`
`sp2/0
`CHo
`ns0
`CHo
`ns0
`ns0**
`CHo
`
`CHo
`
`Human igG1κ
`Humanized igG1κ
`Human igG1κ
`Human igG2κ
`Human igG1l
`Human igG1κ
`Human igG1κ
`
`iL12/23
`iL6r
`Cd20
`rAnK-L
`BLys
`B. anthrasis PA
`CtLA-4
`
`2009 (2009)
`2009 (2010)
`2010 (2009)
`2010 (2010)
`2011 (2011)
`nA (in review)
`2011 (2011)
`
`Chimeric igG1κ; conjugated
`to monomethyl auristatin E
`
`Cd30
`
`in review (2011)
`
`in review (in review)
`HEr2
`CHo
`Pertuzumab (Pending)
`Humanized igG1κ
`note: information current 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 syncy-
`tial 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).
`
`voluntarily withdrawn from both mar-
`kets in 2009 because of the risk of side
`effects, including progressive multifocal
`leukoencephalopathy.12,13
`The European Union and the US
`are not necessarily the first or only mar-
`kets for therapeutic mAbs (Table 3).
`Nimotuzumab, a humanized mAb that
`targets EGFR, was developed at the
`Center of Molecular Immunology in
`
`Cuba. The mAb is marketed in over 20
`countries, including Brazil, India and
`China, as a treatment for head and neck
`cancer or glioma, but it is not approved in
`the EU, US or Japan.14 Mogamulizumab
`is a defucosylated humanized anti-
`CC chemokine receptor 4
`(CCR4)
`antibody developed by Kyowa Hakko
`Kirin Co., Ltd.15 The mAb is approved
`in Japan as a treatment for adult T-cell
`
`and
`
`peripheral
`
`leukemia-lymphoma
`T-cell lymphoma.
`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, bispe-
`cific antibodies, engineered antibodies
`and antibody fragments or domains. The
`commercial pipeline includes ~350 mAbs
`now being evaluated in clinical studies
`
`414
`
`mAbs
`
`Volume 4 issue 3
`
`© 2 0 11 La n d e s B io s cie n ce .
`D o n o t d is trib u te .
`
`Genzyme Ex. 1039, pg 923
`
`

`

`Table 2. therapeutic monoclonal antibodies withdrawn or discontinued from marketing in the European Union or United states
`International proprietary name (Trade name) Manufacturing cell line
`Type
`Target
`First EU (US) approval year
`Muromonab-Cd3 (orthoclone oKt3®)
`Hybridoma
`Murine igG2a
`Cd3
`1986* (1986)
`nebacumab (Centoxin®)
`Human igM
`1991* (nA)
`Hybridoma
`Endotoxin
`Edrecolomab (Panorex®)
`Hybridoma
`Murine igG2a
`EpCAM
`1995* (nA)
`daclizumab (Zenapax®)
`ns0
`iL2r
`1999 (1997)
`Humanized igG1κ
`Gemtuzumab ozogamicin (Mylotarg®)
`ns0
`Cd33
`nA (2000)
`Humanized igG4κ
`Efalizumab (raptiva®)
`CHo
`Cd11a
`2004 (2003)
`Humanized igG1κ
`note: 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).
`
`Table 3. therapeutic monoclonal antibodies approved outside the European Union or United states
`Target
`International proprietary name (Trade name)
`Manufacturing cell line
`Type
`nimotuzumab (theraCiM®, BioMAB-EGFr®)
`ns0
`EGFr
`Humanized igG1κ
`CCr4
`[not found]
`Mogamulizumab
`Humanized igG1κ
`note: information current as of March 30, 2012. Abbreviations: CCr, chemokine receptor; EGFr, epidermal growth factor receptor.
`
`First approval year
`1999
`2012
`
`around the world as treatments for many
`indications, including cancer, immuno-
`logical disorders and infectious diseases.16
`The compendium of marketed therapeu-
`tic antibodies may thus be substantially
`larger in the future.
`
`Acknowledgments
`The author thanks Marjorie Shapiro and
`Mike Clark for providing detailed descrip-
`tions and references for the Sp2/0 and
`NS0 cell lines.
`
`2.
`
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`www.landesbioscience.com
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`mAbs
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`415
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`© 2 0 11 La n d e s B io s cie n ce .
`D o n o t d is trib u te .
`
`Genzyme Ex. 1039, pg 924
`
`