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INTRODUCTION
Cytokines are not produced constitutively. Indeed, cytokines are usually pro-
duced upon stimulation and are secreted by a variety of cell types, and distinct cy-
tokines often have redundant or overlapping functions. They are extremely potent
biomolecules acting at a picomolar, sometimes femtomolar range and may have mul-
tiple (pleiotropic) actions on different target cells. Cytokine released by a cell may
act in a short radius on its own (autocrine) or on other cells (paracrine), thus provid-
ing a means for cross-talk at the cellular level (FIG . 1).
Common structural features of interleukins make it possible to group cytokines
within “families,” and tremendous progress in the cloning of genes for cytokine re-
ceptors and their characterization has led to the recognition that cytokine receptors
may be grouped into four principal families based on common structural features.
Most of these receptors form heterodimers, but some form homodimers or heterot-
rimers. Interestingly, many of the multiple chain receptors form subfamilies with one
chain shared by all members of the subfamily. Due to their multiple functions, in-
cluding regulatory and effector function in many diseases, these molecules, their re-
ceptors, and their signal transduction pathways are promising candidates for
therapeutic interference.
Advances in the understanding of the role of cytokines in immune and inflamma-
tory disorders have led to the development of cytokine-based therapies. Therapies
Address for correspondence: Frank Brombacher, Institute for Infectious Disease and Molecu-
lar Medicine, University of Cape Town, S1. 27, Observatory 7925, Anzio Road, South Africa.
Voice: +27-21-406-6616\6147; fax: +27-21-406-6029.
brombac@uctgsh1.uct.ac.za
Ann. N.Y. Acad. Sci. 1056: 16–29 (2005). © 2005 New York Academy of Sciences.
doi: 10.1196/annals.1352.002
16
CUTLER & BROMBACHER: CYTOKINE THERAPY 17
have been developed with the express aim to block/inhibit or restore the activity of
specific cytokines. A variety of approaches have been employed to produce thera-
peutics with the aim of manipulating cytokine function. Cytokines have been cloned
and produced in recombinant form; coupled to toxin, recombinant cytokine and
receptor molecules have been fused to the Fc portion of human IgG1 or to albumin
to stabilize and increase the serum half-life of the protein. Natural and synthetic
antagonist proteins have been cloned/produced to interfere with ligand/receptor
interaction. Cytokines delivered by gene therapy and antisense oligonucleotide treat-
ment are also being assessed. Currently, the most utilized approach to cytokine ther-
apy is that of blocking or neutralizing cytokine action with monoclonal antibodies
(mAbs) (TABLE 1a and b). Mouse mAbs with specificity for human cytokines have
been “humanized” by grafting the mouse CDR onto the Fc portion of the human
IgG1. Fully human anticytokine mAbs have now been approved for clinical use
(TABLE 1a).
Drugs that block inflammatory cytokines, such as tumor necrosis factor (TNF)-
α, are among the most successful therapeutics approved for clinical use.1–3 Of pa-
tients with rheumatoid arthritis (RA), 60–70% exhibit amelioration of disease upon
treatment with anti-TNF-α. Fusion proteins of sTNF receptor4 and interleukin (IL)-
1Rα antagonist5 are also routinely used in the treatment of RA. It has become appar-
ent that TNF blockers are more efficient than therapies aimed at IL-1 antagonism or
blocking. The scope of therapy using TNF-α and IL-1 blockers/antagonists is now
evolving to target other inflammatory diseases. Targeting inflammatory cytokines
has been a fruitful approach in treating inflammatory autoimmune disease. This suc-
cess has led to the development of mAbs targeting a number of cytokines/cytokine
18 ANNALS NEW YORK ACADEMY OF SCIENCES
TABLE 1a. Cytokine therapies approved for clinical use and further clinical trial
Clinical
Trade name/ trial phase/ Ref/
Cytokine Drug code Application outcome Company Link
IL-1Rα Recombinant Kineret / Rheumatoid arthri- Approved Amgen 5
IL-1Rα Anakinra tis (RA)
antagonist Sepsis Approved
Osteoarthritis Phase II
IL-2 Recombinant Proleukin Metastatic renal cell Approved Chiron 6
IL-2 carcinoma
Metastatic mela- Approved
noma
Non-Hodgkin’s lym- Phase II
phoma
IL-2 Humanized Daclizamab Renal transplanta- Licensed PDL/
IL-2Rα-chain tion Roche
blocking mAb Asthma Phase II
GvHD Phase III [1]
Multiple sclerosis Phase II 38
HIV Phase I [2]
Psoriasis Phase I/II [3]
Ulcerative uveitis Halted [4]
Humanized Simulect / Renal transplanta- Licensed Novartis 39
IL-2Rα-chain Basiliximab tion
blocking mAb
IL-11 Recombinant Oprelvekin / Chemotherapy- Approved Genetics 34
IL-11 Neumega induced thrombo- Institute,
cytopenia Inc/
Crohn’s disease Phase III Wyeth
RA Phase II
Psoriasis Phase II
Colitis Phase I
TNF-α Human anti- Adali- RA Approved CAT/ 3
TNF-α mAb mumab/ Juvenile RA Phase II Abbott
Humira/ Ankylosing Phase III
D2E7 spondylitis
Psoriatic arthritis Phase III
Crohn’s disease Phase III
Chronic plaque pso- Phase II
riasis
TNF-α Humanized Remicade RA Approved Centocor 1, 2
anti-TNFα /Infliximab Crohn’s disease Approved
mAb Ulcerative colitis Phase II
Psoriasis Phase II
Psoriatic arthritis Phase II
Ankylosing Phase II
spondylitis
Juvenile idiopathic Phase II
arthritis
Pediatric Crohn’s Phase II
disease
CUTLER & BROMBACHER: CYTOKINE THERAPY 19
TABLE 1a. Cytokine therapies approved for clinical use and further clinical trial
Clinical
Trade name/ trial phase/ Ref/
Cytokine Drug code Application outcome Company Link
TNF-α Soluble p75 Etanercept/ RA Approved Amgen 4
TNF recep- Enbrel Juvenile RA Approved
tor-Fc Ankylosing Approved
fusion spondylitis
Psoriatic arthritis Approved
Psoriasis Approved
Severe plaque Approved
psoriasis
IFN-γ Bioengi- Actimmune Chronic granuloma- Approved Inter- 12
neered IFN-γ− tous disease mune
1b Osteoporosis Approved Pharma 40
Idiopathic pulmo- Phase III
nary fibrosis
Ovarian cancer Phase III
IFN-α IFN-α−con-1 Infergen Hepatitis C Approved Intermune 9
Pharma
IFN-α IFN-α−n3 leu- Alferon-N HPV gental warts Approved Hemi 10
kocyte derived Hepatitis C Phase II/III sperx
West Nile virus Phase II/III Bio-
HIV Phase I/II pharma
IFN-α Pegylated Pegasys Chronic hepatitis C Approved Roche
IFN-α−2a Hepatitis B Phase III/ 8
Filed
IFN-α Recombinant Roferon-A Hairy cell leukemia Approved Roche 7
IFN-α−2a Kaposi’s sarcoma Approved
Chronic myleloid Approved
leukemia
Chronic hepatitis C Approved
IFN-α Recombinant Intron-A Hairy cell leukemia Approved Schering- 7
IFN-α−2b Kaposi’s sarcoma Approved Plough
Chronic hepatitis B/ Approved
C
Malignant mela- Approved
noma
Follicular lymphoma Approved
Condylomata acumi- Approved
nata
IFN-α PEG recombi- PEG Intron Hepatitis C Approved Schering-
nant IFN-α− Malignant mela- Phase III Plough
2b noma
IFN-β IFN-β−1a Avonex Relapsing multiple Approved Biogen 13
sclerosis Idec
IFN-β IFN-β−1a Rebiferon Relapsing multiple Approved Serono 13
sclerosis
Chronic hepatitis C Phase III
20 ANNALS NEW YORK ACADEMY OF SCIENCES
TABLE 1a. Cytokine therapies approved for clinical use and further clinical trial
Clinical
Trade name/ trial phase/ Ref/
Cytokine Drug code Application outcome Company Link
IFN-β IFN-β−1b Betaseron Early/relapsing Approved Berlex 13
multiple sclerosis
GM-CSF Recombinant Leukine/Sar- Leukemia Approved Schering-
GM-CSF gramostim Bone marrow/stem Approved AG
cell transplants
Crohn’s disease Phase III
[1]http://www.clinicaltrials.gov/show/NCT00053976 (GvHD).
[2] http://www.clinicaltrials.gov/ct/show/NCT00080431?order=5.
[3] http://www.clinicaltrials.gov/ct/show/NCT00050661?order=10.
[4] http://www.pdl.com/applications/press_releases.cfm?newsId=241.
receptors, such as IL-6, IL-8, IL-18, and gamma interferon (IFN-γ) (TABLE 1b) in a
variety of clinical conditions.
Another approach to cytokine therapy that has been applied successfully is treat-
ment using recombinant cytokines. IL-2 has been used in cancer,6,7 various deriva-
tives of IFN-α in viral infection and cancer,8–10 IL-11 in the treatment of post-
chemotherapy induced thrombocytopenia,11 IFN-γ in cancer and osteoporosis,12 and
IFN-β in multiple sclerosis13 (TABLE 1a). Therapy using recombinant cytokines has
also been unsuccessful in some cases. Recombinant IL-10 provided no beneficial
therapy over side effects in a number of settings (TABLE 1b). However, this potent
immunosuppressive cytokine may yet have some therapeutic application.14 Recom-
binant IL-12 can also induce adverse side effects.15
[1] http://www.amgen.com/rnd/pipeline.html
[2] http://www.hopkins-arthritis.som.jhmi.edu/edu/eular2004/ra-treatments-il1.html
[3] http://www.transgene.fr/us/product_pipeline/iframe_ad_il2.htm
[4] http://www.transgene.fr/us/page.php?fam=1&rub=3&iframe=product_pipeline/
iframe_mva_muc1_il2.htm
[5] http://www.transgene.fr/us/page.php?fam=1&rub=2&iframe=product_pipeline/
iframe_mva_hpv_il2.htm
[6] http://www.clinicaltrials.gov/ct/show/NCT00076180
[7] Preclinical Evaluation of Bay 16-9996 a Dual Il-4/Il-13 Receptor Antagonist N. Fitch, M.
Morton, A. Bowden, M.-C. Shanafelt, A. Shanafelt, G. Wetzel, J. Moy Biotechnology Research,
Bayer Corp, Berkeley, CA. Abstract J.A.C.I 107: 2 section 209
[8] http://www.pdl.com/applications/press_releases.cfm?newsId=68
[9] http://www.gsk.com/financial/product_pipeline/docs/pipeline.pdf
[10] http://www.abgenix.com/ProductDevelopment/?view=DevelopmentStrategy
[11] http://www.cambridgeantibody.com/html/technology_products/product_pipeline/
abt874__treatment_for_autoimmune_
inflammatory_disorders
[12] http://www.nci.nih.gov/search/ViewClinicalTrials.aspx?cdrid=67489&ver-
sion=patient&protocolsearchid=1344505
[13] http://www.cambridgeantibody.com/html/technology_products/product_pipeline/cat354
[14] http://www.amrad.com.au/Files/IL-13a1%20-%20Aug%202004.pdf
[15] www.serono.com/pipeline/pipeline.jsp?major=2 - 35k - 28 Dec 2004
[16] http://www.clinicaltrials.gov/ct/gui/show/NCT00085904
[17] http://www.zymogenetics.com/clinical/il-21.html
[18] http://www.clinicaltrials.gov/ct/show/NCT00037700?order=1
[19] http://www.clinicaltrials.gov/ct/show/NCT00043706
[20] http://www.cambridgeantibody.com/html/technology_products/product_pipeline/trabio
treatment_for_scarring_following_glaucoma_surgery
[21] http://www.antisense-pharma.com/products/f_products.htm
Allergies are reproducible reactions of the immune system against stimuli, which
are tolerated by most people. Most allergies are mediated by Th2-dependent immune
mechanisms. These are characterized by very fast responses towards the antigen,
typically within minutes, with most or all of the Th2 cytokines (i.e., IL-4, IL-5, IL-
9, and IL-13) possibly involved in the disease phenotype, therefore being potential
targets for cytokine therapy against allergic diseases (FIG . 2). After initial contact
with the allergen (sensitization phase), symptoms are felt within minutes (effector
phase) in immediate type (type 1) allergies. This type includes common reactions
such as hay fever, some food allergies, and allergies against house dust mites, animal
hair, and insect stings, among others. Allergic asthma is a complex disorder charac-
terized by local and systemic allergic inflammation associated with a chronic pul-
monary eosinophilia and elevated serum IgE levels causing mast cell activation,
airway remodeling, and reversible airway obstruction. Asthma symptoms, especially
shortness of breath, are primarily related to airway obstruction, and death is almost
invariably due to asphyxiation. Increased airway hyperresponsiveness (AHR) and
mucus hypersecretion by goblet cells are two of the principal causes of airway
obstruction observed in asthmatic patients. IL-4 is known to be the central promoter
of Th2 development in vivo and in vitro. However, recent studies by us and others
have challenged a sole in vivo role of IL-4 in Th2 differentiation, as in the absence
of IL-4 or its receptor, Th2 differentiation was still present.25 Despite these observa-
tions, the importance of IL-4 in allergic reactions has been confirmed in experimen-
tal murine models, mostly using OVA as the allergen. Indeed, in the absence of IL-
4–mediated functions, either by in vivo blocking of IL-4 or its receptor or by genet-
ically disrupting the gene, OVA-sensitized and challenged mice showed reduced
AHR, eosinophilic inflammation, IgE production, and mastocytosis.26–30 Much
conflicting data have been gathered on the role of IL-5 in allergic asthma, despite its
clear role as a differentiation factor for eosinophils,31–33 with rather disappointing
results in clinical studies in asthma targeting IL-5.34 Monoclonal antibodies specific
for IL-9 are now being used in phase I clinical trials in asthma. The possible role of
IL-13 had remained elusive until 1998 when we and others demonstrated that IL-13
is a key factor in the asthmatic phenotype, able to directly induce goblet cell hyper-
plasia and AHR in mice35,36 (FIG . 2). These results prompted discussions about IL-
13 as a promising target for anti-asthmatic therapies, resulting in three drug leads
now in clinical phase I trials (TABLE 1b). My group is currently involved in the
establishment of several cell-type–specific knockout mouse models to further define
the role of IL-4 and IL-13 in infectious and allergic diseases (TABLE 3).
26 ANNALS NEW YORK ACADEMY OF SCIENCES
FIGURE 2. Proposed allergic asthma model. Role of Th2 cells, effector cells, and
cytokine network in the pathogenicity of asthma. Thp, parental T helper cell; Th2, T helper 2
cell; B, B lymphocyte; E, eosinophil; G, goblet cell; M, mast cell; APC, antigen presenting cell.
FUTURE PERSPECTIVES
ACKNOWLEDGMENTS
This work was supported in part by the Medical Research Council (MRC) and
National Research Foundation (NRF) of South Africa. F.B. is a holder of a Wellcome
Trust Research Senior Fellowship for Medical Science in South Africa (Grant
056708/Z/99).
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