mAbs
`
`ISSN: 1942-0862 (Print) 1942-0870 (Online) Journal homepage: http://www.tandfonline.com/loi/kmab20
`
`Antibody-based therapeutics to watch in 2011
`
`Janice M. Reichert
`
`To cite this article: Janice M. Reichert (2011) Antibody-based therapeutics to watch in 2011 ,
`mAbs, 3:1, 76-99, DOI: 10.4161/mabs.3.1.13895
`To link to this article: https://doi.org/10.4161/mabs.3.1.13895
`
`Copyright © 2011 Landes Bioscience
`
`Published online: 01 Jan 2011.
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`eee
`mAbs3:1, 76-99; January/February 2011; © 2011 Landes Bioscience
`
`Antibody-based therapeutics to watch in 2011
`
`Janice M. Reichert
`
`Tufts Centerfor the Study of Drug Development; Boston, MA USA
`
`This overview of 25 monoclonal antibody (mAb) and five Fc fusion protein therapeutics provides brief descriptions
`of the candidates, recently published clinical study results and on-going Phase 3 studies. In alphanumeric order, the
`2011 therapeutic antibodies to watch list comprises AIN-457, bapineuzumab, brentuximab vedotin, briakinumab,
`dalotuzumab, epratuzumab,
`farletuzumab, girentuximab (WX-G250), naptumomab estafenatox, necitumumab,
`obinutuzumab, otelixizumab, pagibaximab, pertuzumab, ramucirumab, REGN88,
`reslizumab, solanezumab, T1h,
`teplizumab, trastuzumab emtansine, tremelimumab, vedolizumab, zalutumumaband zanolimumab.In alphanumeric
`order, the 2011 Fc fusion protein therapeutics to watch list comprises aflibercept, AMG-386, atacicept, Factor VIII-Fc
`and Factor IX-Fc. Commercially-sponsored mAband Fc fusion therapeutics that have progressed only as far as Phase
`2/3 or 3 were included. Candidates undergoing regulatory review or products that have been approved mayalso be
`in Phase 3 studies, but these were excluded. Dueto the large body of primary literature about the candidates, only
`selected references are given andresults from recent publications and articles that were relevant to Phase 3 studies are
`emphasized. Current as of September 2010, the information presented herewill serve as a baseline against which future
`progress in the developmentof antibody-based therapeutics can be measured.
`
`Introduction
`
`inotuzumab ozogamicin,
`(WX-G250),
`are 25 “antibodies to watch” in 2011.
`The complete list ofthe 25 mAbsin alpha-
`ipilimumab, mepolizumab, naptumomab
`numeric order bytarget appears in Tables
`The pharmaceutical and biotechnology
`estafenatox, ocrelizumab, otelixizumab,
`pagibaximab, pertuzumab, ramucirumab,
`industry is currently investing substan-
`1, 3 and 5.
`Information about mAbs that are in
`tial resources in the development of anti-
`reslizumab,
`solanezumab,
`tanezumab,
`trastuzumab
`emtansine,
`regulatory review or approved for mar-
`teplizumab,
`body-based therapeutic products. Novel
`vedolizumab and zalutumumab.
`keting by the United States Food and
`monoclonal antibodies (mAbs) have been
`Nine of the 26 mAbs on the 2010list
`entering clinical studyat a rate of over 40
`Drug Administration (US FDA)arelisted
`were not included in the 2011 version for
`in Tables 2, 4 and 6 for comparison.
`per year since 2007 and new productsare
`being approvedata steady pace.! Hundreds
`Two mAbs, catumaxomab and nimotu-
`various reasons. Two mAbs (belimumab
`zumab, that are approved for marketing
`ofmAbs,as well as novelFc fusion proteins
`and ipilimumab) advanced to regulatory
`outside of the US should also be noted.
`review, all studies of two mAbs(galix-
`that are composed of binding peptides or
`proteins fused to the Fc domain of immu-
`Catumaxomab
`(Removab®;
`Fresenius
`imab and 131-I mAb 81C6) were sus-
`is
`a
`pended or terminated and development
`noglobulin G, are undergoing clinical
`Biotech GmbH, Trion Pharma)
`mouse/rat-derived, bispecific mAb that
`of five (figitumumab,
`inotuzumab ozo-
`study as potential treatments for disease.
`By the end of 2010, a total of 30 of these
`targets the epithelial cell adhesion mol-
`gamicin, mepolizumab, ocrelizumab and
`ecule (EpCAM)on tumorcells and CD3
`candidates (25 mAb and five Fe fusion
`tanezumab) reverted to Phase 2 studies.
`on T cells. The product was approved
`protein) were in Phase 2/3 or Phase 3
`New to the 2011 list are eight mAbs that
`for marketing in the European Union in
`entered a first Phase 3 clinical studyor re-
`clinical studies sponsored by commercial
`April 2009 for treatment of patients with
`entered a Phase 3 study since September
`firms, and these are included on the 2011
`malignantascites. Catumaxomabis in an
`2009.
`In alphanumeric order by mAb
`antibody-based therapeutics to watchlist.
`on-going Phase 3 study [NCT00822809]
`A total of 26 mAbs in commercially-
`name, these are: AIN-457, brentuximab
`as a treatment of malignantascites due to
`sponsored Phase 2/3 or Phase 3 clinical
`vedotin, necitumumab, obinutuzumab,
`studies were included on the 2010 anti-
`epithelial cancer.
`REGN88, T1h, tremelimumab and zano-
`bodies to watch list.? In alphanumeric
`(BIOMAb-EGFR,
`Nimotuzumab
`limumab. Two (trelimumab and zano-
`order by mAb name,
`these candidates
`limumab) were previously in Phase 3
`Thera-CIM; Biocon, YM_Biosciences,
`were: 131-I mAb 81C6, bapineuzumab,
`studies that were terminated prior
`to
`Oncosciences)
`is
`a humanized IgGl
`mAb that targets the epithelial growth
`belimumab,
`briakinumab,
`dalotu-
`2009, and so were not on the “antibodies
`
`
`zumab, epratuzumab,—farletuzumab, to watch in 2010”list. As a consequence factor receptor (EGFR).* The product is
`
`figitumumab, galiximab, girentuximab
`of these changes to the 2010 list,
`there
`approved for marketing in a number of
`
`*Correspondenceto: Janice M.Reichert; Email: janice.reichert@tufts.edu
`Submitted: 10/11/10; Accepted: 10/11/10
`DOI: 10.4161/mabs.3.1.13895
`
`76
`
`mAbs
`
`Volume3 Issue 1
`
`

`

`Table 1. Monoclonal antibodies in Phase 3 studies as treatments for cancer indications
`
`Sponsoring company
`
`‘tunational
`non-proprietary name
`
`Target and type
`
`Indication of Phase 3 study
`
`Active Biotech Research
`
`Naptumomabestafenatox
`
`Steere Eon: ae =ae
`enterotoxin A
`
`Advanced renalcell carcinoma
`
`EDITOR’S CORNER
`
`FDAdesignations
`for Phase 3 study
`salicaticey
`
`Wilex AG
`
`Girentuximab
`
`Carbonic anhydraseix; |gG1 aea Oo
`carcinoma
`
`TenX Biopharma/Genmab
`
`Zanolimumab
`
`CD4; IgG!
`
`CutaneousT-cell lymphoma
`
`FT,O
`
`ShcaNetance)
`Seattle Genetics
`
`Obinutuzumab
`Brentuximab vedotin
`
`Pfizer
`
`Genmab
`
`ImClone
`Morphotek
`Genentech
`Genentech
`
`Tremelimumab
`
`Zalutumumab
`
`Necitumumab
`Farletuzumab
`Trastuzumab emtansine
`Pertuzumab
`
`CD20; IgG1
`Coe eer comgata a
`monomethylauristatin E
`
`CTLA-4; IgG2
`
`EGFR;IgG1
`
`EGFR; IgG1
`Folate receptora; IgG1
`HER2; IgG1 conj. to DM1
`HER2; IgG1
`
`Merck, Pierre Fabre
`
`Dalotuzumab
`
`IGF-1R; IgG1
`
`Imclone Systems/EliLilly
`
`Ramucirumab
`
`VEGFR2; IgG1
`
`Chronic lymphocytic leukemia
`Hodgkin lymphoma
`
`Metastatic melanoma
`
`Head and neck cancer
`
`Non-small cell lung cancer
`Ovarian cancer
`etrkta pt eiaeeue
`reast cancer
`Metastatic breast cancer
`
`Metastatic colorectal cancer
`Metastatic gastric or
`pesteeenpigsel uection
`adenocarcinoma; breast can-
`cer; hepatocellular carcinoma
`
`FT,O
`
`FT
`
`Oo
`
`Information current as of September1, 2010. CD,cluster of differentiation; CTLA, cytotoxic T-lymphocyte-associated antigen; EGFR, epidermal growth
`factor receptor; Fab, antigen-binding fragment; FDA, US Food and Drug Administration;FT,fast track designation; HER2, human epidermal growth
`factor receptor; IGF-1R, insulin-like growth factor-1 receptor; O, orphan drug designation; VEGFR2, vascular endothelial cell growth factor receptor2.
`International non-proprietary naming convention: -umab, human; -zumab, humanized; -ximab, chimeric; -momab, murine.
`
`Table 2. Monoclonal antibodies in FDA review or approved as treatmentsfor cancer indications
`International
`Indication under review or
`oneCarica varia
`fia serneed
`Ofatumumab
`Chronic lymphocytic leukemia
`Tositumomab-!131
`Non-Hodgkin lymphoma
`
`Target and type
`CD20; human IgG1
`CD20; murine IgG2a
`
`Trade name
`Arzerra
`Bexxar
`
`FDAapprovalyear
`2009
`2003
`
`2002
`
`1997
`
`2000*
`2001
`
`CD20; murine IgG1
`
`Non-Hodgkin lymphoma
`
`CD20; chimeric IgG1
`
`Non-Hodgkin's lymphoma
`
`Acute myeloid leukemia
`Chronic myeloid leukemia
`
`Ibritumomabtiuxetan
`
`Rituximab
`
`Gemtuzumabozogamicin
`Alemtuzumab
`
`Ipilimumab
`
`Panitumumab
`
`Cetuximab
`Trastuzumab
`Bevacizumab
`
`Zevalin
`
`Rituxan
`
`Mylotarg
`Campath-1H
`
`Pending
`
`Vectibix
`
`Erbitux
`Herceptin
`Avastin
`
`CD33; humanized IgG4
`CD52; humanized IgG1
`
`CTLA-4; human IgG!
`
`EGFR; human IgG2
`
`EGFR; chimeric lgG1
`HER2; humanized IgG1
`VEGF; humanized IgG1
`
`Advanced melanoma eeps
`
`Colorectal cancer
`
`Colorectal cancer
`Breast cancer
`Colorectal cancer
`
`2006
`
`2004
`1998
`2004
`
`Information current as of September1, 2010. “Voluntarily withdrawn from US market. CD, cluster of differentiation; EGFR, epidermal growth factor
`receptor; CTLA, cytotoxic T-lymphocyte-associated antigen; FDA, US Food and Drug Administration; HER2, human epidermal growth factor receptor;
`PDUFA,Prescription Drug User Fee Act; VEGF, vascular endothelial growth factor. International non-proprietary naming convention: -umab, human;
`-zumab, humanized;-ximab, chimeric; -momab, murine.
`
`www.landesbioscience.com
`
`mAbs
`
`77
`
`

`

`Table 3. Monoclonal antibodies in Phase 3 studies as treatments for immunological indications
`International
`non-proprietary name
`
`Sponsoring company
`
`Target and type
`
`Indication of Phase 3 study
`
`FDAdesignations
`for Phase 3 study
`indication
`
`Millennium/Takeda
`
`Tolerx
`
`Macrogenics/Eli Lilly
`
`Biocon/CIMAB SA
`
`Vedolizumab
`
`Otelixizumab
`
`Teplizumab*
`
`Tih
`
`a4 7 integrin; lgG1 ot or ae
`ulcerative colitis
`
`CD3;1gG1
`
`CD3;1gG1
`
`Type 1 diabetes mellitus
`
`Type 1 diabetes mellitus
`
`CD6; humanized IgG1
`
`Psoriasis
`
`Immunomedics/UCB
`
`Epratuzumab
`
`CD22; IgG1
`
`Systemic lupus erythematosus
`
`Cephalon
`Regeneron
`
`Reslizumab
`REGN88
`
`IL-5; IgG4
`Eosinophilic esophagitis
`IL-6R; human IgG1 el Seeeaeeee
`arthritis
`
`Oo
`
`Oo
`
`FT
`
`Oo
`
`Plaquepsoriasis
`IL-12/23; |gG1
`Briakinumab**
`Abbott
`Uveitis
`IL-17A; human IgG1
`AIN-457
`Novartis
`Information current as of September1, 2010. CD,cluster of differentiation; FDA, US Food and Drug Administration;FT,fast track designation;IL,
`interleukin; O, orphan drug designation.International non-proprietary naming convention: -umab, human; -zumab, humanized. *Note addedin proof:
`In a press release issued in October 2010,Lilly announcedthat the primary endpointin the PROTEGE study (NCT00385697) had not been met and
`enrollment and dosing in the PROTEGE and PROTEGEEncore (NCT00920582)studies were suspended. **Note added in proof: In a press release issued
`in October 2010, Abbott announcedthat marketing applications for briakinumab werefiled in the US and Europe during the third quarter of 2010.
`
`Table 4. Monoclonal antibodies in FDA review or approvedas treatments for immunological indications
`International
`Indication underconsiderationorfirst
`non-proprietary name
`approved
`
`Target and type
`
`Trade name
`
`Belimumab
`
`Eculizumab
`
`Pending
`
`Soliris
`
`Muromonab-CD3
`
`Orthoclone Okt3
`
`Simulect
`
`B-lymphocyte stimulator;
`humanIgG1
`
`Systemic lupus erythematosus
`
`C5; humanized IgG2/4
`CD3; murine lgG2a
`
`Paroxysmal nocturnal hemoglobinuria
`
`Reversalof kidney transplant rejection
`
`FDAapprovalyear
`
`Pending (PDUFA action
`date Dec. 9, 2010)
`2007
`
`1986*
`
`1998
`
`Basiliximab
`
`Daclizumab
`
`Efalizumab
`Tocilizumab
`
`Ustekinumab
`Canakinumab
`
`Omalizumab
`
`Natalizumab
`
`Golimumab
`
`Certolizumab pegol
`
`Adalimumab
`Infliximab
`
`Zenapax
`
`Raptiva
`Actemra
`
`Stelara
`llaris
`
`Xolair
`
`Tysabri
`
`Simponi
`
`Cimzia
`
`Humira
`Remicade
`
`IL2R; chimeric IgG1
`
`IL2R; humanized IgG1
`
`CD11a; humanized IgG1
`IL6R; humanized IgG1
`
`1L12/23; human IgG1
`
`IL1B; human IgG1
`
`IgE; humanized IgG1
`
`Preventionof kidney transplant rejection
`Prevention of kidney transplant rejection
`Psoriasis
`
`Rheumatoidarthritis
`
`Plaque psoriasis
`Muckle-Wells syndrome
`Asthma
`
`«4 integrin; humanized IgG4
`
`Multiple sclerosis
`
`TNF; human IgG1
`
`TNF; humanized Fab,
`pegylated
`
`TNF; human IgG1
`
`TNF; chimeric IgG1
`
`Rheumatoid andpsoriatic arthritis,
`ankylosing spondylitis
`
`Crohn disease
`
`Rheumatoidarthritis
`Crohn disease
`
`1997*
`
`2003*
`2010
`
`2009
`2009
`
`2003
`
`2004
`
`2009
`
`2008
`
`2002
`1998
`
`Information current as of September 1, 2010. *Voluntarily withdrawn from US market. C5, complement5; CD,cluster of differentiation; FDA, US Food
`and Drug Administration;IL, interleukin; PDUFA, Prescription Drug User Fee Act; TNF, tumor necrosis factor. International non-proprietary naming
`convention: -umab, human; -zumab, humanized;-ximab, chimeric; -momab, murine.
`
`countries, e.g., India, Cuba, Argentina,
`Columbia, Ivory Coast, Gabon, Ukraine,
`Peru and Sri Lanka as a treatment for
`patients with squamous cell carcinoma
`of the head and neck; Cuba, Argentina,
`Philippines and Ukraine as
`a
`treat-
`ment for glioma in pediatric and adult
`patients and China for patients with
`
`nasopharyngeal cancer. Nimotu-zumab
`is
`in commercially-sponsored, ongoing
`Phase 3 studies in patients with glioblas-
`toma multiforma (NCT00753246) and
`patients with advanced nasopharyngeal
`cancer (NCTO1074021).
`With six products in FDA review or
`approved and five candidates in Phase 3
`
`studies, Fc fusion protein therapeutics are
`a growing class of antibody-based mol-
`ecules that have been included on the
`2011 watch list. In alphanumeric order,
`the 2011 Fe fusion protein therapeu-
`tics to watch list comprises aflibercept,
`AMG-386,atacicept, Factor VIII-Fc and
`Factor IX-Fe (Table 7). For comparison,
`
`78
`
`mAbs
`
`Volume3 Issue 1
`
`

`

`Table 5. Monoclonalantibodies in Phase 3 studies as treatments for non-traditional indications
`
`Sponsoring company
`
`international
`non-proprietary name
`
`Target and type
`
`Indication of Phase 3 study
`
`FDA designations
`for Phase 3 study
`indication
`
`Biosynexus
`y
`Lilly
`
`Pfizer, Janssen
`
`Pagibaximab
`9
`Solanezumab
`
`Bapineuzumab
`
`Lipoteichoic acid; IgG1
`P
`a
`Amyloid beta; IgG1
`
`Amyloid beta; IgG1
`
`Eeeeameee Oo
`very low birth weight neonates
`Alzheimerdisease
`
`Alzheimerdisease
`
`FT
`
`Information current as of September1, 2010. FDA, US Food and Drug Administration;FT, fast track designation; O, orphan drug designation. Interna-
`tional non-proprietary naming convention: -zumab, humanized; -ximab, chimeric.
`
`Table 6. Monoclonal antibodies in FDA review or approved as treatments for non-traditionalindications
`International
`Indication under consideration orfirst
`Tears Trade name
`ae
`Raxibacumab
`Pending
`Anthraxinfection
`
`Target and type
`B. anthrasis PA; human |gG1
`
`FDAapprovalyear
`Pending
`
`Abciximab
`Denosumab
`
`Motavizumab
`
`Palivizumab
`
`Ranibizumab
`
`Reopro
`Prolia
`
`Pending
`
`Synagis
`
`Lucentis
`
`GPllb/Illa; chimeric lgG1 Fab
`RANK-L; human IgG2
`
`Prevention of blood clots in angioplasty
`Boneloss
`
`1994
`2010
`
`RSV; humanized IgG1
`
`Prevention of respiratory syncytial virus infection
`
`Pending
`
`RSV; humanized IgG1
`
`Prevention of respiratory syncytial virus infection
`
`VEGF; humanized IgG1 Fab
`
`Macular degeneration
`
`1998
`
`2006
`
`Information current as of September1, 2010. FDA, US Food and Drug Administration; GP; glycoprotein; PA, protective antigen; RANK-L, receptoracti-
`vator of NFxb ligand; RSV,respiratory syncytial virus; TNF, tumor necrosis factor; VEGF, vascular endothelial cell growth factor.
`
`Table 7. Fc fusion protein therapeutics in Phase 3 studies for any indication
`Sponsorin
`International
`en h 9
`non-proprietary
`pany
`or code name
`
`Description
`
`Regeneron/Sanofi-
`.
`aventis/Bayer
`
`.
`Aflibercept
`
`Extracellular domains of VEGFR1 and
`VEGFR2fused to Fc of human IgG1
`
`FDAdesigna-
`tions for Phase 3
`studyindication
`
`FT (for
`symptomatic
`.
`malignant
`ites)
`ee
`
`Indications of Phase 3 study
`
`Ovarian cancer with symptomatic
`malignantascites, prostate, smallcell
`,
`ao
`lung, colorectal and pancreatic can-
`cers’; wet age-related macular degen-
`eration; centralretinal vein occlusion
`
`Epithelial ovarian, primary peritoneal
`or fallopian tube cancers’
`
`.
`Systemic lupus erythematosus
`
`Severe hemophilia A
`
`ee
`
`.
`Atacicept
`
`FactorVIII-Fe
`
`Angiopoietin-1 and -2 binding peptide
`fused to Fc of human IgG1
`Extracellular domain of transmembrane
`.
`.
`rs
`activator and calcium-modulating ligand
`.
`.
`interactor fused with Fc of human Ig
`FactorVIII fused to Fc of human IgG1
`
`oe
`
`.
`ZymoGenetics/
`Merck Serono
`
`Biogen eeeel
`Orphan Biovitrum
`Biogen Idec/Swedish
`Orphan Biovitrum
`
`FactorIX-Fe
`
`Factor IX fused to Fc of humanIgGl
`
`Hemophilia B-associated hemorrhagic
`events
`
`O
`
`Data current as of September 2010.‘Five separate Phase 3 studies, with onein eachindication. “Single Phase 3 study [NCT01204749] in which patients
`mayhaveanyof theseindications;listed on clinicaltrials.gov as not yet open for participation as of September 2010. FDA, United States Food and Drug
`Administration; FT,fast track; O, orphan drug; VEGFR, vascular endothelial growth factor receptor.
`
`fusion proteins
`information about Fc
`that are in regulatory review or approved
`for marketing by the FDA are listed
`in Table 8.
`and
`Commercially-sponsored mAb
`Fe fusion protein therapeutics that have
`progressed only to Phase 2/3 or Phase 3
`were included. Candidates undergoing
`
`regulatory review or products already on
`the market mayalso be in Phase 3 studies,
`but these were excluded. MAbsin devel-
`opment sponsored solely by academic,
`governmentand non-profit organizations
`were also excluded. Due to the large body
`of primary literature about the 30 candi-
`dates on the 2011 watch list, only selected
`
`references are given, and results from
`recent publications and articles that were
`relevant to Phase 3 studies are empha-
`sized. Current as of September 2010, the
`information presented here will serve as a
`baseline against which future progress in
`the development of antibody-based thera-
`peutics can be measured.
`
`www.landesbioscience.com
`
`mAbs
`
`79
`
`

`

`Table 8. Fc fusion protein therapeutics approvedin the US as treatmentsfor any indication
`International
`non-proprietary name
`
`Tredalneres
`
`Description
`
`Yearoffirst
`Indication underreview orfirst approved Eee
`Prophylaxis of organ rejection and preser-
`vation of a functioningallograft in adult
`patients receiving renal transplants
`
`Pending
`
`Belatacept
`
`Pending
`
`Abatacept
`
`Orencia
`
`Rilonacept
`
`Arcalyst
`
`Alefacept
`
`Amevive
`
`Etanercept
`
`Romiplostim
`
`Enbrel
`
`NPlate
`
`Data current as of September2010.
`
`Extracellular domain of CTLA-4 fused to
`Fc of a human IgG1
`
`Extracellular domain of CTLA-4 fused to
`Fc of a human IgG1
`Extracellular domain of interleukin-1
`receptorfused to Fc of human IgG1
`Extracellular domain of LFA-3 fused to Fc
`of a human IgG1
`Extracellular domain of tumor necrosis
`factor receptor fused to Fc of human IgG!
`
`Moderate-to-severely active rheumatoid
`aoe
`arthritis
`
`Cryopyrin-associated periodic syndromes
`
`Treatment of adults with moderate-to-
`severe plaque psoriasis
`
`Moderate-to-severely active rheumatoid
`sae
`arthritis
`
`2005
`
`2008
`
`2003
`
`1998
`
`2008
`
`Thrombopoietin-binding peptide fused to
`Fc of human IgG1
`
`Thrombocytopenia in chronic immune
`thrombocytopenic purpura patients
`
`Eight New mAbs
`in Phase 3 Clinical Studies
`
`and Sézary syndrome.® Zanolimumab
`The Hx-CD4-007 (NCT00071071)
`study included 25 early stage (IB-IIA)
`was designated a Fast Track candidate as
`mycosis fungoides patients, 11 and 14 of
`a treatment for CTCL patients who have
`which were administered 280 and 560 mg
`failed current
`therapy and an Orphan
`Of the eight mAbs that entered (or re-
`
`
`
`entered) Phase 3 clinical studies recently, zanolimumab,_respectively.’drug specifically for treatment of mycosis doses of
`fungoides by the FDA.
`five (zanolimumab, obinutuzumab, bren-
`The Hx-CD4-008
`(NCT00071084)
`Zanolimumab was assessed in two
`study included a total of 22 patients
`tuximab vedotin,
`tremelimumab, neci-
`tumumab) are potential
`treatments for
`Phase 2 studies as a treatment for early
`dosed as follows: nine late stage (IIB-
`(Hx-CD4-007; NCT00071071) and late
`IVB) mycosis fungoides and four Sézary
`cancer indications (Table 1) and three
`(Tlh, REGN88, AIN-457) are being
`(Hx-CD4-008; NCT00071084)
`stage
`syndrome patients
`received 280 mg
`doses of zanolimumab and four
`late
`CTCL.’ Initiated in 2003, both of these
`studied as treatments for immunological
`multicenter Phase 2 studies were non-ran-
`stage (IIB-IVB) mycosis fungoides and
`disorders (Table 3). Four of these mAbs
`five Sézary syndrome patients received
`target antigens that are unique compared
`domized, uncontrolled (i.e., no placebo
`980 mgdoses of zanolimumab.’ An objec-
`to those targeted by mAbproductsalready
`arm wasincluded), open label and single
`on the market or in regulatory review.
`group assignment. Prior to enrollment,
`tive response, based on composite assess-
`The antigens are: CD4 (target of zanoli-
`ment of the index lesion disease severity
`patients in both studies had been previ-
`mumab), CD30 (target of brentuximab
`score, was obtained by 13 mycosis fungoi-
`ously treated with at least one treatment
`vedotin), CD6 (target of T1h) and inter-
`regimen and had failed or relapsed. For
`des patients (3 of 20 at 280 mg doselevel,
`leukin (IL)-17A (target ofAIN-457).
`7 of 14 at 560 mg dose level and 3 of 4 at
`both studies, patients were administered
`980 mg dose level). One of four and one
`Zanolimumab
`(HuMax-CD4,
`intravenous(iv) doses ofzanolimumabover
`MDX-CD4; TenX Biopharma)
`is
`a
`15 min on a weekly basis. Seventeen infu-
`offive Sézary syndromepatients who were
`human IgGl mAb that targets CD4 on
`sions were given over 16 weeks, with a
`administered 280 mg or 980 mg doses of
`the surface of T cells. The mAb has been
`follow up visit four weeks later. Response
`zanolimumab,
`respectively, obtained an
`shownto inhibit or deplete T cells through
`rates, duration of responses,
`relief of
`objective response. The response rate of
`a variety of mechanismssuchasalteration
`symptomsandthe safety profile of the
`56% in the high dose group was obtained
`of T-cell
`receptor signal
`transduction,
`mAb were evaluated in the 38 mycosis
`with a median response of 81 weeks.
`Fe-dependent CD4 receptor down-mod-
`fungoides patients and nine Sézary syn-
`Increased titers of anti-drug antibodies
`ulation and antibody dependent cellular
`drome patients who enrolled in the two
`were observed in only one patient. Adverse
`cytotoxicity (ADCC). Zanolimumabhas
`studies. The studies were designed as
`events (AEs) included inflammatory skin
`been evaluated as a treatmentfor a variety
`single arm evaluations of 280 mg doses of
`reactions and infections; nine infections
`of diseases characterized by T-cell disor-
`were deemed drug-related although no
`zanolimumab, but data review indicated
`ders, including rheumatoid arthritis, pso-
`that T-cell depletion might be inadequate.
`dose relation was apparent.
`riasis and lymphoma. The current focus of
`Additional study arms with doses of 560
`A Phase
`3.
`study (Hx-CD4-110;
`Phase 3 clinical development is on cuta-
`mg for mycosis fungoides patients and
`NCT00127881) of zanolimumab as a
`neous T-cell lymphomas (CTCLs), which
`980 mgfor Sézary syndromepatients were
`treatment for mycosis fungoides started
`then added.
`are rare lymphomaspresenting primarily
`by Genmabin 2005 was discontinued in
`2008 due to slow enrollment and a need
`in the skin and include mycosis fungoides
`
`mAbs
`
`Volume 3 Issue 1
`
`

`

`progression free survival. Secondary out-
`or Waldenstrom macroglobulinemia (one
`by the companyto reserve resources at
`patient). No dose-limiting toxicity was
`that time. TenX Biopharma acquired the
`come measures include overall survival,
`observed. The most common AEs were
`mAbin 2010 and re-initiated enrollment
`complete response, overall response and
`infusion-related
`reactions;
`six minor
`best response. An estimated 360 patients
`in the study, whichis designed as non-ran-
`infections were observed. The pharmaco-
`domized, open label, dose escalation,fol-
`will be enrolled and the estimated primary
`kinetics of the mAb showeda dose-depen-
`completion date is January 2015.
`lowed by open label and single arm. Adult
`Brentuximab_vedotin
`dent increase in exposure, but significant
`patients (18 years or older) with mycosis
`(SGN-35;
`fungoides (Stage IB-IVB) or Sézary syn-
`inter- and intra-patient variability was
`Seattle Genetics, Millennium) is a chime-
`noted. At the time ofthe report, 7 of 12
`drome whoarerefractory or intolerant to
`ric IgGl
`immunoconjugate that targets
`bexarotene and one other standard ther-
`patients had responded to treatment by
`CD30, which is expressed at high levels on
`apy will receive 12 weekly infusions. The
`day85. The objective response rate (ORR)
`activated lymphocytes. The immunocon-
`primary outcome measure is efficacy as
`was 58%, with complete response in three
`jugate comprises Seattle Genetic’s mAb
`measured byphysician’s global assessment
`patients (25%) and partial response in
`cAC10 (SGN-30) conjugated to the anti-
`four patients (33%).!°
`tubulin agent monomethyl auristatin E
`(PGA); the estimated date for final data
`Obinutuzumab in combination with
`collection for the PGA is February 2011.
`through a peptide linkerthatis selectively
`cleaved after internalization into cells.'!
`chlorambucil is undergoing evaluation in
`Obinutuzumab (RO5072759, GA101;
`Results for Phase 1 studies of bren-
`Genentech/Roche),
`a
` glyco-engineered
`a Phase 3 study (NCTO01010061) of adult
`anti-CD20 IgGl mAb,
`is undergoing
`(18 years and older) patients with previ-
`tuximab vedotin have been reported. A
`evaluation in combination with other
`ously untreated CLL. The open label,
`Phase 1 dose escalation study included 45
`drugs in two Phase 3 studies as a treat-
`randomized study will have three arms:
`patients (42 with Hodgkin lymphoma,
`mentfor non-Hodgkin lymphoma (NHL)
`(1) 1 g doses of obinutuzumab iv admin-
`two with systemic anaplastic large cell lym-
`and chronic lymphocytic leukemia (CLL).
`istered on days 1, 8 and 15 in cycle 1 and
`phomaand one with angioimmunoblastic
`Obinutuzumabdiffers from the marketed
`on day 1 of cycles 2-6 in combination
`T-cell lymphoma) who were administered
`anti-CD20 ofatumumab and rituximab
`with 0.5 mg/kg chlorambucil adminis-
`immunoconjugate at doses ranging from
`in its mechanisms of action. The mAbis
`tered orally on day 1 and 15 ofeach cycle;
`0.1-3.6 mg/kg as 2 h iv infusions every
`three weeks.’ The observed maximum
`a Type II antibody and so has a distinct
`(2) 375 mg/m? rituximab iv administered
`on day 1
`in cycle 1 and 500 mg/m? on
`effector
`function profile that
`includes
`tolerated dose was 1.8 mg/kg on this dos-
`reduced binding to Clq and lowerlevels
`day 1 of cycles 2-6 in combination with
`ing schedule and the terminal elimination
`half-life was 5.0 + 1.8 days at the 1.8 mg/kg
`ofCDC butpotentinduction ofcell death
`chlorambucil administered as in arm 1;
`dose. AEs that occurred in 20% or more
`through caspase-independent apoptosis.®
`(3) chlorambucil only administered as in
`Enhanced activity was correlated with a
`arm 1. The primary outcome measure is
`of patients were fatigue, pyrexia, nausea
`modified elbow hinge residue (valine at
`progression-free survival as assessed every
`and diarrhea. Neutropenia related to dose
`Kabat position 11 instead of leucine).?
`two weeks while patients are on study
`level was observed. One patient admin-
`treatment, 28 days after last dose and at
`istered 3.6 mg/kg who developed febrile
`Obinutuzumab also contains a glyco-
`intervals for at least 5 years of follow-up.
`neutropenia died 14 days after the first
`engineered Fe region, with bisected, com-
`plex,
`non-fucosylated
`oligosaccharides
`dose. Of 28 patients who received doses of
`Secondary outcome measures
`include
`response rates, duration of response and
`attached to asparagines 297, that allows
`1.2 mg/kg or greater and could be evalu-
`disease-free survival in patients with com-
`ated, 46%obtained an objective response;
`the mAb to bind with increased affinity
`to FeyRIII.?
`plete response, overall survival, molecu-
`seven patients (25%) obtained a complete
`remission rate.
`Obinutuzumabis being evaluated as a
`lar remission, minimal residual disease,
`monotherapy in an on-going open-label,
`safety profile, pharmacokinetics of obinu-
`dose-escalating Phase 1/2 study with a
`tuzumab andpatient reported outcomes.
`randomized Phase 2 part (NCT00517530)
`The estimated enrollment is 786 patients
`of patients with CD20* malignant disease.
`and the estimated study completion date
`The study was initiated in September
`is February 2022.
`study (NCT-
`3
`2007 andresults for the first 12 patients
`A second Phase
`were
`reported in December 2008.!°
`01059630; GADOLIN)is investigating
`Obinutuzumab was administered by iv
`the efficacy and safety ofobinutuzumabin
`combination with bendamustine in adult
`infusion at a flat dose on days 1, 8 and 22
`and subsequently every three weeks for a
`patients with rituximab-refractory, indo-
`total of nine infusions. The dose was esca-
`lent NHL. This open label, randomized
`lated according to a 3 + 3 design; doses
`study will compare results for the com-
`ranging from 50-800 mg were adminis-
`bination of drugs with those observed for
`tered to patients who hadfollicular NHL
`patients treated with bendamustine alone.
`(nine patients), diffuse large B-cell lym-
`Nodosing information is currently avail-
`phoma(one patient), CLL (one patient)
`able. The primary outcome measure is
`
`A more frequent schedule of brentux-
`imab vedotin doses was evaluated in a
`dose escalation Phase 1 study with a 3 +3
`design. A total of 17 adult patients (25-27
`years) who had been pretreated (median
`of four prior therapies, with 65% having
`received an autologous stem cell
`trans-
`plant) were administered brentuximab
`vedotin weekly at doses of 0.4, 0.6, 0.8
`and 1 mg/kg.’ Grade 1/2 rash, nausea
`and peripheral neuropathy were the most
`common AEs; Grade 3 diarrhea occurred
`in one patient. Three (of four) and four
`(of six) patients who received the 0.8 and
`1.0 mg/kg doses, respectively, obtained a
`complete response, with an observed time
`
`www.landesbioscience.com
`
`mAbs
`
`81
`
`

`

`to response of approximately eight weeks
`for patients in the 1 mg/kg dose group.
`A total of seven heavily pretreated
`patients who were administered brentux-
`imab vedotin during one of three Phase 1
`studies experienced relapse and were
`retreated with the
`immunoconjugate.
`Results of the case series, which included
`six Hodgkin lymphomapatients and one
`anaplastic large cell
`lymphoma patient,
`were reported in 2010.'* The adult patients
`(28-39 years) were administered IV infu-
`sions of brentuximab vedotin at doses
`of 1 mg/kg once per week or 1.8 mg/kg
`every three weeks; the seven patients expe-
`rienced eight
`retreatments. Treatment
`related AEs were Grade 1/2. Of AEs
`that occurred in more than one patient,
`three patients developed upper respira-
`tory tract infection and peripheral sensory
`neuropathy was observed in two patients.
`Objective responses were observed in six
`retreatments (two complete responses and
`four partial responses) and occurred 5-13
`weeksafter the start of retreatment.
`Top-line
`results were
`reported in
`September 2010 for a pivotal Phase 2
`study (NCT00848926) of brentuximab
`vedotin in patients with relapsed or
`refractory Hodgkin lymphoma who had
`previously received autologous stem cell
`transplants.'° Patients (12 years and older)
`were administered 1.8 mg/kg doses of
`brentuximab vedotin every three weeksfor
`up to 16 total doses. Of 102 patients who
`participated in the study, 75% achieved an
`objective response. The mean duration of
`response wasgreater than 6 months.
`Brentuximab vedotinis currently being
`evaluated in a randomized, double-blind
`placebo-controlled Phase 3 AETHERA
`study
`(NCT01100502;
`SGN35-005).
`The immunoconjugate and best
`sup-
`portive care (BSC)
`is being compared
`to placebo and BSC in the treatment of
`patients at high risk of residual Hodgkin
`lymphoma following autologousstem cell
`transplant. Adult patients (18 years or
`older) are administered either 1.8 mg/kg
`doses of brentuximab vedotin or placebo
`byiv infusion every 21 days. The primary
`outcome measure is progression-free sur-
`vival and secondary outcome measures
`are overall survival, incidence of adverse
`events and laboratory abnormalities and
`incidence of anti-therapeutic antibodies.
`
`The estimated enrollment is 322 patients
`and the primary completion dateis esti-
`mated to be June 2013.
`The safety of brentuximab vedotin is
`being evaluated in an open label, non-ran-
`domized Phase 2/3 study (NCT01196208)
`in patients with progressive Hodgkin
`lymphoma. Adult patients (18 years and
`older) are administered 1.8 mg/kg doses
`of brentuximab vedotin by iv infusion
`every 21 days. The primary outcome mea-
`sures are the incidence of AEs and labora-
`tory abnormalities through 1 month after
`last dose. Enrollment is by invitation to
`patients who are randomly allocated to
`placebo in the Phase 3 SGN35-005 study
`(NCT01100502).
`Tremelimumab (CP-675,206; Pfizer),
`a human IgG2 mAb,targets the cyto-
`toxic T lymphocyte-associated antigen-4
`(CTLA-4)that acts as a negative regulator
`for T cells, thereby modulating the dura-
`tion and intensity ofanimmuneresponse.'®
`Tremelimumabha