Review

Integrins as therapeutic targets

Simon L. Goodman1 and Martin Picard2
1
2

Department of Cellular Pharmacology Oncology Platform, Merck KGaA, Frankfurterstrasse 250, 64271 Darmstadt, Germany
Global Clinical Development Unit Oncology, Merck KGaA, Frankfurterstrasse 250, 64271 Darmstadt, Germany

Integrins are a large family of molecules that are central

regulators in multicellular biology. They orchestrate
cellcell and cellextracellular matrix (ECM) adhesive
interactions from embryonic development to mature
tissue function. Diverse human pathologies involve
integrin adhesion, including thrombotic diseases, inflammation, cancer, fibrosis and infectious diseases.
Integrins are exciting pharmacological targets because
they are exposed on the cell surface and are sensitive to
pharmacological blockade, but the scale of current
efforts involving integrin therapeutics continues to
surprise. Several therapeutics targeting integrins are
effective drugs: five have been approved for use in
clinic, with combined sales of over $1.5 billion in
2010 (based on company reports from that year). We
gathered information from three major drug-trial databases and found that 260 anti-integrin drugs have
entered clinical trials. Here we overview integrins as
drug targets and focus on cancer.
Integrins: an overview
Integrins are heterodimeric cell-surface proteins. Each
integrin has multiple activation states, many have splicing
variants, and their expression, glycosylation and activity
vary with cellular context [1]. Many different heterodimers
can be expressed on a single cell, and each can interact with
multiple intracellular signaling cascades. Depending on
the cellular microenvironment, the biological effect of ligating or activating an integrin can vary dramatically
[1,2]. The regulation of integrin activity is complex. They
are primed by extracellular stimuli that initiate intracellular signals which convert (inside-out) the extracellular
domains to a high-affinity state [3]. Integrins have no
intrinsic enzymatic activity but, following binding to extracellular ligands, they become activated, can cluster on
the cell surface, and undergo conformational changes
which propagate across the membrane (outside-in) to
activate cytoplasmic kinase- and cytoskeletal-signaling
cascades. These in turn control cell attachment, movement, growth and differentiation, and survival [1,2]. In
addition, integrins interact with growth factors and their
receptors. Signaling by pathologically relevant receptor
tyrosine kinases, including vascular endothelial growth
factor receptor 2 (VEGFR2), epidermal growth factor receptor (EGFR) and platelet-derived growth factor receptor
(PDGFR), is modulated by integrins [4,5]. Integrin ligation
protects cells from experimental stresses, such as irradiation, and their blockade can enhance the cytotoxic efficacy
of radiation- and chemotherapeutics [6,7]. Integrins bind to
Corresponding author: Goodman, S.L. (Simon.L.Goodman@merckgroup.com).

microorganisms and can regulate the turnover of other

cell-surface receptors [1,8,9].
However, the crucial pharmacological issue is: in precisely which pathological micro-environment will a particular integrin play the dominant role, and thus be a target?
In most disease indications, and for most integrins, this
question is only partially answered, and in practice can
only be answered in controlled clinical trials.
The 24 known integrin heterodimers can be classified
as arginineglycineaspartate (RGD)-binding, the a4
family, leukocyte adhesion integrins, laminin-binding,
and I-domain collagen-binding; this classification also
clusters the most frequently targeted indications (Table
1). Integrins mediate proteinprotein interactions via
relatively small amino acid sequences, which aids drug
design. Classically, the RGD sequence [10] is recognized
by eight integrins, the four collagen-binding integrins
recognize triple helical GFOGER sequences, and a4 integrins recognize LDV (Table 1) [1,9]. The atomic basis of
ligand recognition of some collagen and RGD-binding
integrins is known [11], and preclinically potent and specific inhibitors have been developed [12,13]. Not surprisingly, many (120) companies have attempted to develop
drugs to modify integrin function.
Clinical trials overview
The integrins which are actively targeted and the stage of
trials last reported (cut-off January 2012) are shown in
Figure 1. We focus on the majority of drugs that target
integrins directly, not indirectly (e.g., via their expression
or the intracellular signaling pathways they control).
Figure 1 summarizes the status of trials reported to be
active (72 trials), or discontinued (46 trials); 140 are
in limbo, with no development reported (i.e., for up to
15 years). Many targeting approaches have been attempted,
ranging from classical small molecules, peptides and engineered antibodies, to antagonists derived from snake
venoms. To date, most efforts have focused on four integrins
gpIIbIIIa, a4b1, avb3 and LFA-1 and have produced five
registered drugs, targeting gpIIbIIIa (abciximab, tirofiban,
intrifiban), LFA-1 (efalizumab, subsequently withdrawn;
discussed below), and a4b1 (natalizumab). Drugs that have
reached late-stage trial and their last reported status are
summarized in Table 2.
Integrins as targets
Parenteral therapies using antibody and other proteinbased therapies that cannot cross the cell membrane are
possible or even desirable with integrins because the
ligand-binding sites are exposed on the cell surface,

0165-6147/$ see front matter 2012 Elsevier Ltd. All rights reserved. http://dx.doi.org/10.1016/j.tips.2012.04.002 Trends in Pharmacological Sciences, July 2012, Vol. 33, No. 7

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Table 1. Integrin subfamilies cluster major therapeutic indications (after Hynes [1], Barczyk [9], and Cox [13])
Integrin class
a4 Family
a4b1
a4b7
a9b1
Leukocyte cell adhesion
aLb2
a;b2
aXb2
aDb2
aEb7
RGD-binding
gpIIbIIIa
a5b1
a8b1
anb1
anb3
anb5
anb6
anb8
I domain: collagen binding
a1b1
a2b1,
a10b1, a11b1
LN binding
a3b1
a6b1,a7b1
a6b4

Clinically targeted in?

Main ligands a

MS, autoimmune, Crohns, IBD

MS, autoimmune, arthritis
Cancer

VCAM-1, FN
MAd-CAM-1
VCAM-1, Opn, VEGF-C,-D

Inflammation, psoriasis, stroke, ischemia, fibrosis

Inflammation, autoimmune
Inflammation
Inflammation
Inflammation

ICAM-1,-2,-3
iC3b, Fbg
iC3b, Fbg
ICAM-3, VCAM-1
E-cadherin

Thrombosis, stroke, myocardial ischemia

Cancer, AMD
None
Cancer
Cancer, osteoporosis
Cancer
Fibrosis, transplant rejection, cancer
Cancer

Fbg, vWf
FN
Npn, FN, VN
VN, FN
VN, Opn, vWf, FN, Fbg b
VN
FN, TGF-b1,-3
FN, TGF-b1,-3

Fibrosis, cancer
Fibrosis, cancer
None

Col
Col
Col

None
None
None

LN-5
LN-1, -2
LN-2, -4, -5

Abbreviations: Col, collagens; Fbg, fibrinogen; FN, Fibronectin; LN, laminin; Npn, nephronectin; Opn, osteopontin; VN, vitronectin; vWF, von Willebrand factor.

Among many other ligands.

47

11
21

41

51
4X

X2

gp2b3a

L2

whereas the effector sites are shielded within the cell [14].
Integrins have been targeted by ligand-mimetic antagonists and by allosteric inhibition of their ligand-binding
sites [12,13]. Although many natural integrin inhibitors
from snake and other venoms (e.g., echistatin) seemed
potential therapeutics, they are immunogenic, and none
have progressed beyond early clinical development. The
preclinical development of effective and specific small-molecule inhibitors has been possible largely due to knowledge
of integrin recognition sites in the ECM. The usual pharmacological issues of bioavailability, specificity and offtarget effects are joined by the integrin-specific issues of
extreme functional complexity, mentioned in the introduction, and for this reason it can often be hard to pinpoint
their exact function in disease biology. By contrast, the
complexity of the integrins presents a chance for a
single inhibitor to modulate a given disease in multiple
beneficial ways.

Key:

3
6

Biological
Small molecules
Antibodies

TRENDS in Pharmacological Sciences

Figure 1. The current distribution of integrins as therapeutic targets and the stages
of related clinical trials. If targeting affects all a chains (ax) or all b chains (bx) the
trial is classified accordingly (e.g., intetumumab affects all av integrins
independently of associated b chains and is classed under avbx). Trials
discontinued (light blue); at Phase I (dark blue); at Phase II (pale orange); at
Phase III (mid orange); or approved drugs (brown). Symbols: small molecules and
peptides (circles yellow); antibodies (triangles); biologicals (cubes). Symbols with
black centers represent discontinued trials.

406

a4-Family integrins
When activated, a4-family integrins mediate cellcell
adhesions crucial to immune function [15]. a4b1 mediates
late stages of leukocyte diapedesis (movement out of the
circulatory system) whereas a4b7 controls T-cell homing.
a4b1 binds to fibronectin splice variants at the CS-1 domain, and to vascular cell adhesion protein 1 (VCAM-1)
which is expressed on activated endothelia near sites of
inflammation, whereas a4b7 binds to mucosal vascular
addressin cell adhesion molecule 1 (MAd-CAM) to capture

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Trends in Pharmacological Sciences July 2012, Vol. 33, No. 7

Table 2. Integrin inhibitors in late-stage (Phase III or Phase II) clinical studiesa
Clinical phase
Approved

Phase III

Phase II

Indication b
MS

Target
a4bx c

Drug
Natalizumab

Thrombosis
Thrombosis
Thrombosis

gpIIbIIIa
gpIIbIIIa
gpIIbIIIa

Abciximab
Tirofiban
Intrifiban

IBD, UC, Crohns

UC, Crohns
Dry eye, conjunctivitis
Immunosuppression
Stroke, ischemia
Thrombosis
Thrombosis
Diagnostics
Thrombosis
Cancer

a4bx
a4b7
aLb2
aLb2
aLb2
gpIIbIIIa
gpIIbIIIa
gpIIbIIIa
gpIIbIIIa
avb3, avb5

AJM-300
Vedolizumab
SAR-1118
Odulimomab
Rovelizumab
Alnidofibatide
Orbofiban
DMP-444 (Tc99m)
Lefradafiban
Cilengitide

Arthritis
Crohns
IBD, MS, RA, asthma,
Crohns
Arthritis, asthma
Ulcerative colitis
Asthma, rhinitis
HIV infection
IS, psoriasis
Thrombosis
AP, stroke, thrombosis
Restenosis, thrombosis
Thrombosis
Thrombosis
Cancer, Crohns
Cancer, AMD
Arthritis, cancer,
osteoporosis,
psoriasis, restenosis, RA
Cancer
Cancer: diagnostics
Cancer: diagnostics
Kidney TR, PF
Cancer
Osteoporosis
AMD, diabetic retinopathy

a4b1
a4bx
a4bx

MDL-819767
TRK-170
firategrast

a4bx
a4b7, aEb7
a4b1
aLb2
aLb2
gpIIbIIIa
gpIIbIIIa
gpIIbIIIa
gpIIbIIIa
gpIIbIIIa
a5b1
a5b1
avb3

RO-27-0608
Etrolizumab
RBx-7796
Cytolin
BMS-587101
MK-0852
Cromafiban
FK-633
Elarofiban
SR-121787
ATN-161
Volociximab
Etaracizumab

avbx
avb3, avb5
avb3
avb6
avbx
avb3
avbx, a5b1

Intetumumab
Fluciclatide (18F)
99
mTc-Maraciclatide
STX-100
EMD-525797
MRL-123
AGR-1001

Synonyms
Tysabri, Antegren, AN-100226,
BG-00002
ReoPro, Clotinab, CentoRx
L-700462, MK-383, Aggrastat
Eptifibatide, SB-1, Sch-60936,
Integrelin
MLN-02, LDP-02

23F2G, LeukArrest
RPR-109891, Klerval
SC-57099B, CS-511
RP-444
BIBU-104
EMD 121974, EMD 85189,
NSC-707544
HMR-1031
SB-683699, T-0047
Valategrast, R411
Pro-145223, RG-7413
RBx-4638, clafrinast

L-367073
CT-50352
FR-144633
RWJ-53308

M-200, EOS-200-4
MED-522, hLM609,
Vitaxin-2, Abegrin
CNTO-95
GE-135, [18F]-AH-111585
NC100692
3G9
DI17E6

Drug class
Hu-mAb

Status
L

Refs.
[18]

Chi-mAb-Fab
SM
cPep

L
L
L

[23,61]
[25]
[62]

oSM
Chi-mAb
SM
Chi-mAb
Chi-mAb
Pep-der
SM
Diag
SM
cPep

A
A
A
ndr
ndr
A
A
ndr
ndr
A

[63]
[64]
[22]

SM
oSM
oSM

A
A
A

[67]
[68]
[69]

SM
hu-Mab
SM
hu-mAb
oSM
cPep
SM
SM
SM
SM
Pep
mAb
mAb

A
A
ndr
A
ndr
A
ndr
ndr
ndr
ndr
A
A
A

[70]
[17]

mAb
Diag
Diag
hu-mAb
hu-mAb
SM
cPep

A
A
A
A
A
ndr
A

[52]
[58]
[57]
[42]
[51]

[65]
[66]

[44]

[71]
[72]

[50]
[39]
[32]

[73]

Citations are provided for all projects reported currently active in clinic.

Abbreviations: A, trials active; AP, angina pectoris; cPep, cyclic peptide; Chi-mAb-Fab, chimeric monoclonal antibody, Fab fragment; Diag, diagnostic reagent; HIV, human
immunodeficiency virus; Hu-mAb, humanized monoclonal antibody; IS, ischemic stroke; L, launched/drug approved for clinical use; mAb, monoclonal antibody; ndr, no
development reported, drug not discontinued, but trials not apparently active; oSM, orally available small molecule; Pep-der, peptide derivative; PF, pulmonary fibrosis; RA,
rheumatoid arthritis; SM, small molecule; TR, transplant rejection.

bx indicates that all associated b chains are targeted.

antigen-presenting cells in post-capillary venules of peripheral lymphoid tissue [1,16]. a4 integrins have been
extensively targeted by drugs selective for one or both
receptors (Table 2). a9b1 is being pre-clinically investigated as a target affecting metastasis. The b7 integrins are
being targeted in Phase II trial for therapy of ulcerative
colitis (UC) (Mab Etrolizumab [17]).
The inappropriate activation of leukocytes in tissues by
cytokines drives many autoimmune diseases, including
multiple sclerosis (MS), Crohns disease, and inflammatory
bowel disease (IBD) [16]. A series of inhibitors have been
developed to prevent these cytokine-driven processes, and

the migration and arrest of T cells in peripheral lymphoid

tissues [12,13]. The engineered pan-a4 antibody natalizumab has been approved for recurrent MS, and it has proved
to be a breakthrough for relapsed MS patients by reducing
the frequency of relapse, a unique therapeutic result [18].
This achievement was overshadowed by its temporary
withdrawal following the occurrence (at >1:1000 patients)
of an exceedingly rare virus-induced neurodegenerative
process, progressive multifocal leukoencephalopathy
(PML) [19]. However, after reassessment in 2010, the
European Medicines Agency (EMA) concluded that the
benefits outweighed the risks for patients treated with
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Review
natalizumab, and it was re-approved with implementation
of appropriate warning and safety measures. Several
small-molecule inhibitors of a4 integrins are in development as followers of natalizumab. a4b7 is also a coreceptor
for human immunodeficiency virus (HIV) [20], and further
therapeutic opportunities may thus await a4 inhibitors.
b2-Series integrins
b2-series integrins are expressed only on leukocytes and,
following priming by cytokines, they regulate inflammatory responses together with the a4 integrins [15]. In 2000,
LFA-1 (aLb2) was effectively targeted in psoriasis by the
antibody efalizumab [21], and several other antibodies
against LFA-1 were in development, despite complications related to immunosuppression. However, these programs stopped and efalizumab was withdrawn in April
2009 after several PML cases (occurrence 1:1000) [19]. It is
not yet clear whether LFA-1 inhibitors with different
mechanisms of action may circumvent PML, but clearly
any future systemic usage will need close clinical monitoring. Cytolin, another antibody against LFA-1, is in
Phase II trial for HIV infection. A small-molecule LFA-1
inhibitor (SAR-1118) is entering Phase III trials in ophthalmology to treat dry-eye syndrome [22], where topical
application may reduce the problems seen during systemic
blockade of LFA-1.
aIIbb3 (also known as gpIIbIIIa)
GpIIbIIIa is an RGD-binding integrin that binds fibrinogen, which regulates platelet accumulation into blood clots.
It was a therapeutic target before it was recognized as an
integrin [23]. The inhibitory mAb 7E3 binds to the b3
chain; as abciximab, an engineered (Fab)2 antibody fragment, it enhances the effects of aspirin and heparin in
patients with acute coronary syndromes. It was approved
in 1995 and its use continues in patients with interventive
coronary disease and ischemia. Its long plasma half-life
and specificity are benefits; however, prolonged inhibition
of coagulation is undesirable in many instances and this
limits its use. The efficacy of abciximab encouraged the
development of many parenterally administered smallmolecule drugs targeting gpIIbIIIa (Figure 1, Table 2),
two of which, eptifibatide [24] and tirofiban [25], have been
approved for use in unstable angina and angioplasty. Many
subsequent orally available small molecules failed because
they were partial agonists and gave thrombotic rebound
effects [26]. gpIIbIIIa functions as a hair-trigger, and
therefore a few agonistically activated integrins lead to
activation of the entire platelet, to give physiologically
rapid arrest at a target site, or pathologically, to trigger
thrombosis.
a5b1 and av integrins
a5b1 and av integrins are being targeted for cancer [27]
(below), ophthalmological and orthopedic indications, and
avb3 for osteoporosis [28]. avb3 has also been connected
(as has avb5) to angiogenesis in tumors [27,29], arthritis
[30], psoriasis and age-related macular degeneration
(AMD) [31], and trials in these indications (not AMD) have
been initiated using etaracizumab, an engineered variant
of the avb3-specific Mab LM609 [32], and for AMD using a
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Trends in Pharmacological Sciences July 2012, Vol. 33, No. 7

peptide derivative, AGR-1001. Osteoporosis involves osteoclast bone resorption in which the close contact between
osteoclasts and bone is mediated by avb3 [28]. Small
molecules targeting avb3 in osteoporosis have so far had
modest clinical efficacy (e.g., L-000845704) [33].
Of the four I-domain containing integrin receptors for
collagens and laminins (a1b1, a2b1, a10b1, a11b1), and the
three receptors for laminins (a3b1, a6b1, a7b1) (Table 1)
only drugs targeting a1b1 and a2b1 have reached early
clinical trials. Collagens are major interstitial matrix components and, with laminins, form much of the basement
membrane. Targeting these integrins might interfere not
only with invasive tumor growth and angiogenesis and the
accumulation of inflammatory cells in tissues, but also with
normal physiological processes. This could potentially restrict their therapeutic window. An anti-a1b1 humanized
monoclonal antibody SAN-300 (hAQC2) [34] is currently in
Phase I trials for rheumatoid arthritis, with results expected
in mid-2012. Vatelizumab (GBR-500), a humanized Mab
against a2b1, is in Phase I trials for acute relapse in MS and
IBD, and is reportedly well-tolerated (Company press release: http://www.glenmarkpharma.com/GLN_NWS/PDF/
Glenmark_-_GBR_500_Press_Release.pdf). Little visible effort has been made to target clinically the laminin receptors,
possibly because inhibition of these receptor systems can
cause severe diseases (bullous pemphigoid-like diseases,
Duchenne muscular dystrophy [35]). However, a6b4 is
upregulated in many tumors and interacts with growth
factor receptors relevant in oncology. It has been proposed
as a therapeutic target [36] but no candidate drug development has been described.
Integrin inhibitors in late-stage cancer trials
Cancer is complex, and tumor cells, stromal cells, angiogenic endothelia and immune cells all interact with the
ECM, which plays a central role in solid tumor development. Integrins, which regulate the interactions of tumor
cells with their microenvironment, appear to be key modulators of the interaction. ECM proteins containing RGD
sequences are overexpressed in the provisional ECMs
deposited during tumor development. a5b1 and av integrins are upregulated within the tumor neo-vasculature and
on several classes of tumors, and have been targeted for
drug development [27,37]. Overall, 65 integrin-inhibitory
compounds have been reported as being developed in
anticancer treatments. One compound has already completed recruitment in a pivotal Phase III trial, eight are in
Phase II evaluation, and six are in Phase I clinical development. Five compounds are currently in preclinical evaluation, whereas 38 compounds are reported with a status
of no development. Seven have been discontinued. Of the 15
compounds in clinical development, the majority (n = 12)
target RGD-binding integrins, one attacks I-domain
integrin receptors for collagens and laminins, and two target
a4 integrins (Figure 1, Table 2).
All nine compounds in late-stage clinical development
(Phase II and III) target RGD-binding integrins. The various inhibitors investigated range from compounds specifically blocking a single integrin to those targeting all av
integrins. So far, only one compound has reached Phase III,
the cyclic RGD peptide inhibitor cilengitide [38], and this is

Review
being tested in a clinical trial for the first-line treatment of
the highly aggressive brain tumor glioblastoma (GBM).
Thus, five of the eight integrins that bind RGD
sequences in the ECM are either clinically proven (gpIIbIIIa; discussed above) or strongly suspected (a5b1, avb3,
avb5, avb6) to be therapeutic targets. avb3 was the first
integrin observed to be deregulated in a malignant disease, melanoma, where its expression increases during
the vertical growth phase [1,9,27]. Subsequently avb3
and avb5 were also found to be upregulated in various
tumors and tumor angiogenic blood vessels, and preclinical data have suggested that targeting them might have
antiangiogenic and antitumor effects [27]. The discoveries
that avb6 and avb8 are involved in the activation of latent
TGF-b1 and 3, and might regulate local immune response, and that avb6 is upregulated in some cancers,
indicates that they may also be potential anticancer
targets [5].
a5b1
a5b1 is implicated preclinically both in primary tumor
development and in tumor angiogenesis, which is suspected to be the primary target of antitumor action for
a5b1 inhibitors in vivo. The furthest advanced drug is an
antibody (Voloxicimab; M-200) targeting a5, which is in
Phase II clinical development for malignant melanoma
(single agent; + dacarbacine), non-small-cell lung cancer
[NSCLC (+ erlotinib), renal, ovarian (+ doxorubicin), and
pancreatic cancer (+ gemcitabine) [39]. Voloxicimab has
generally been well-tolerated, without severe drug-related
adverse events. The observed clinical activity has been
encouraging; however, randomized studies are needed to
validate these observations [40]. A new a5b1 inhibitor
(Mab PF-4605412) is currently under investigation in
Phase I. a5b1 small-molecule inhibitors (e.g., JSM-6427)
in development all appear to have been discontinued
[13,41].
avb6
avb6 mono-specific inhibitors, Mabs STX-100 [42] and 264RAD, were in early clinical trial for cancer but are apparently not being actively developed. However, anti-an antibodies, which also inhibit avb6, appear to be more
promising and are in Phase II trials (below).
avb3
avb3 is specifically targeted by the mAb etaracizumab and
the small-molecule MK-0429. Etaracizumab (humanized
engineered mAb LM609; vitaxin, abegrin) [32] has been
investigated in Phase II trials in metastatic castrationresistant prostate cancer (CRPC) and in metastatic melanoma. Further indications investigated with etaracizumab include irinitotecan-refractory colorectal cancer,
breast cancer and leiomyosarcoma. Overall, the safety
profile after systemic long-term avb3 blockade appeared
favorable. The randomized trial in metastatic melanoma
showed that etaracizumab in combination with dacarbacine did not provide a relevant survival benefit compared
to dacarbacine alone [32]. Efficacy results of the randomized study in metastatic prostate cancer have not yet
been reported. The orally administered MK-0429 has

Trends in Pharmacological Sciences July 2012, Vol. 33, No. 7

completed a Phase I/II study in solid tumors with no

reported safety issues [43]. However, no further development has been reported.
avb3 and avb5
Cilengitide (EMD 121974) is a cyclic RGD pentapeptide
which inhibits both avb3 and avb5 integrins [38]. It is
being investigated as an anticancer treatment in highgrade gliomas and in other indications including NSCLC
and head and neck carcinoma [44]. Early results in pancreatic cancer and melanoma were disappointing [45,46].
However, hints of monotherapy activity in metastatic
prostate cancer, NSCLC, and long-lasting objective
responses in late-stage high-grade glioma [47], stimulated
a focus on enhancing efficacy in combination treatments.
The promising results obtained in GBM in several Phase II
trials, both as monotherapy and combination treatment
[48], led to the ongoing CENTRIC study, the first Phase III
trial of an integrin inhibitor in cancer, in partnership with
the European organization for research and treatment of
cancer (EORTC). It investigates cilengitide in newly diagnosed GBM patients in combination with radiation and
chemotherapy (the standard of care: SoC) compared to SoC
alone. The CENTRIC trial focuses on a patient population
defined by a molecular marker (the methylated MGMT
gene promoter), whereas a companion Phase II study
investigates cilengitide in the complementary (unmethylated MGMT gene promoter) patient group [49]. In addition, two large randomized, controlled Phase II trials are
ongoing in NSCLC and squamous cell carcinoma of the
head and neck (SCCHN). So far, the safety profile has been
favorable and encouraging; however, Phase III efficacy
data are not yet available.
a5b1 (avb3 and avb5)
ATN-161 is a five amino acid non-RGD synergy site
peptide [41,50] which is claimed to inhibit avb5, avb3
and a5b1. After initial development for cancer, the drug
was reformulated in 2008. Phase I trials showed favorable
safety, and two Phase II trials combining ATN-161 with
radiation and chemotherapy are reported to be in preparation, one in GBM and one in head and neck tumors.
av
Pan-av inhibition is a potentially attractive anticancer
treatment, considering the roles of avb3 and avb5 [27] and
the link of avb6 and avb8 to TGF-b activation [5]. There
are currently two mAbs in advanced clinical evaluation,
DI17E6 (Phase II) [51], and intetumumab (CNT095) [52]
both as a therapeutic antibody (Phase II) and as a toxin
conjugate (IMGN-388: in Phase I). Both antibodies
bind to the av subunit and inhibit the ligand-binding
functions. DI17E6 is a de-immunized mAb (deglycosylated; no expected antibody-dependent cellular cytotoxicity: ADCC). After Phase I studies demonstrating a
favorable safety profile, randomized Phase II trials in
prostate cancer and colorectal cancer are ongoing. Intetumumab has potential as an immune effector because it is
an IgG1 as well as an av inhibitor (glycosylated; potential
for ADCC). Whether this difference to DI17E6 will be
beneficial or deleterious will only become clear following
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Review
trial evaluation. So far, the safety profiles of both drugs
appear favorable [52,53]. The results of a randomized
Phase II trial of intetumumab in stage IV melanoma
suggest a potential benefit [52], and a Phase III trial
appears to be under consideration. Efficacy results of a
randomized Phase II study in metastatic prostate cancer
are pending. IMGN-388 is intetumumab conjugated to the
maytansinoid cytotoxic agent DM4 and is currently in
Phase I evaluation.
Imaging reagents
Integrins have extracellular ligand-binding sites, and are
therefore not only unique therapeutic targets but also offer
the possibility to investigate target expression in patients
using non-invasive imaging. This has been demonstrated
with RGD-based 18F-PET imaging in a variety of tumor
types, demonstrating selective signals in tumors expressing the av integrins, as validated by immunohistochemistry [54,55]. These results also underline the selective
upregulation in situ of avb3 integrins on tumors compared
to normal tissue and their accessibility from the systemic
circulation. In the future, such imaging reagents may be
useful tools for the selection of potential patients and for
following up the efficacy of anti-integrin treatment [56].
Further work is needed to develop these imaging methods,
and two diagnostic molecules are in clinical Phase II
development (Maraciclatide-Tc-99m recognizing avb3;
18
F-flucitadine detecting av integrins) [57,58]. Other imaging approaches using gadolinium-based magnetic resonance imagingRGD imaging tools are in early
development.
All compounds in late-stage clinical development as
anticancer treatment (n = 7) or cancer diagnostic (n = 2)
target the RGD-binding integrins, which so far appear to
be the most promising for anticancer treatment. Four drug
candidates are mAbs and three are SMs (including cilengitide), with no obvious difference yet seen between classes of
therapeutic molecules. Potentially more relevant, as
highlighted above, is the specific environment and application of RGD-integrin inhibitors. In animal models RGDintegrin inhibitors have convincing antitumor activity as
monotherapy [27,59] or can promote tumor growth under
particular conditions [29]. Meanwhile, orthotopic models
combining RGD-integrin inhibitors with radiotherapy
demonstrated striking synergy [60]. Overall, the benefit
for patients in current clinical studies will reveal what
value anticancer treatments using such approaches might
have. The first rigorous evaluation of an RGD integrin
inhibitor will come from the results of the ongoing Phase
III trial of cilengitide for the treatment of GBM.
In addition to RGD-integrin inhibitors currently in late
stage development, several compounds in Phase I target
other classes of integrins [e.g., GLPG-0187 (avbx + a5b1)
or ELND-002 and EN-396579 (a4b1)] and will provide
further insight in future. In this short review we cannot
consider the many compounds suggested to influence
integrin function indirectly (e.g., the tellurium-based stimulator of lymphokines AS 101, the inhibitor of a2 integrin
expression E-7820, or endostatin, reported to act via integrins, and approved in China for treatment of NSCLC).
Excellent recent reviews have included late-stage integrin
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Trends in Pharmacological Sciences July 2012, Vol. 33, No. 7

clinical projects in a broad range of other indications which

we cannot extensively cover here [12,13].
Concluding remarks
In summary, at least three integrins are proven therapeutic targets (gpIIbIIIa, LFA-1, and a4b1) and many more
are under investigation. Even pharmacological blockade of
failed targets can help to reveal the extraordinary diversity
of integrin biology and, as we have attempted to survey
here, many anti-integrin therapeutics are being actively
investigated, with a substantial number in late-stage clinical trials. Although cell adhesion molecules are, naturally,
superficial, the integrins look likely to play an increasingly
deep role in human therapy.
Acknowledgments
We gratefully acknowledge Dr Stefan Homburg of the Merck literature
research unit for extracting integrin-related trials from company reports
and from the databases of Thomson Reuter Integrity (https://
integrity.thomson-pharma.com/integrity/xmlxsl), Citeline Pharmaprojects
(http://www.citeline.com/products) and Thompson Pharma (http://www.
thomson-pharma.com).

References
1 Hynes, R.O. (2002) Integrins: bidirectional, allosteric signaling
machines. Cell 110, 673687
2 Schwartz, M.A. and Ginsberg, M.H. (2002) Networks and crosstalk:
integrin signalling spreads. Nat. Cell Biol. 4, E65E68
3 Shattil, S.J. et al. (2010) The final steps of integrin activation: the end
game. Nat. Rev. Mol. Cell Biol. 11, 288300
4 Somanath, P.R. et al. (2009) Cooperation between integrin alphavbeta3
and VEGFR2 in angiogenesis. Angiogenesis 12, 177185
5 Margadant, C. and Sonnenberg, A. (2010) IntegrinTGF-beta crosstalk
in fibrosis, cancer and wound healing. EMBO Rep. 11, 97105
6 Zutter, M.M. (2007) Integrin-mediated adhesion: tipping the balance
between chemosensitivity and chemoresistance. Adv. Exp. Med. Biol.
608, 87100
7 Hodkinson, P.S. et al. (2006) ECM overrides DNA damage-induced cell
cycle arrest and apoptosis in small-cell lung cancer cells through beta1
integrin-dependent activation of PI3-kinase. Cell Death Differ. 13,
17761788
8 Caswell, P.T. et al. (2009) Integrins: masters and slaves of endocytic
transport. Nat. Rev. Mol. Cell Biol. 10, 843853
9 Barczyk, M. et al. (2010) Integrins. Cell Tissue Res. 339, 269280
10 Ruoslahti, E. and Pierschbacher, M.D. (1987) New perspectives in cell
adhesion: RGD and integrins. Science 238, 491497
11 Arnaout, M.A. et al. (2007) Structure and mechanics of integrin-based
cell adhesion. Curr. Opin. Cell Biol. 19, 495507
12 Millard, M. et al. (2011) Integrin targeted therapeutics. Theranostics 1,
154188
13 Cox, D. et al. (2010) Integrins as therapeutic targets: lessons and
opportunities. Nat. Rev. Drug Discov. 9, 804820
14 Legate, K.R. and Fassler, R. (2009) Mechanisms that regulate adaptor
binding to b-integrin cytoplasmic tails. J. Cell Sci. 122, 187198
15 Kinashi, T. (2012) Overview of integrin signaling in the immune
system. Methods Mol. Biol. 757, 261278
16 Villablanca, E.J. et al. (2011) Blocking lymphocyte localization to the
gastrointestinal mucosa as a therapeutic strategy for inflammatory
bowel diseases. Gastroenterology 140, 17761784
17 Stefanich, E.G. et al. (2011) A humanized monoclonal antibody
targeting the beta7 integrin selectively blocks intestinal homing of T
lymphocytes. Br. J. Pharmacol. 162, 18551870
18 Pucci, E. et al. (2011) Natalizumab for relapsing remitting multiple
sclerosis. Cochrane Database Syst. Rev. CD007621
19 Major, E.O. (2010) Progressive multifocal leukoencephalopathy
in patients on immunomodulatory therapies. Annu. Rev. Med. 61,
3547
20 Arthos, J. et al. (2008) HIV-1 envelope protein binds to and signals
through integrin a4b7, the gut mucosal homing receptor for peripheral
T cells. Nat. Immunol. 9, 301309

Review
21 Frampton, J.E. and Plosker, G.L. (2009) Efalizumab: a review of its use
in the management of chronic moderate-to-severe plaque psoriasis.
Am. J. Clin. Dermatol. 10, 5172
22 Rao, V.R. et al. (2010) Delivery of SAR 1118 to the retina via ophthalmic
drops and its effectiveness in a rat streptozotocin (STZ) model of
diabetic retinopathy (DR). Invest. Ophthalmol. Vis. Sci. 51, 51985204
23 Coller, B.S. and Shattil, S.J. (2008) The GPIIb/IIIa (integrin aIIbb3)
odyssey: a technology-driven saga of a receptor with twists, turns, and
even a bend. Blood 112, 30113025
24 King, A. (2010) Eptifibatide is noninferior to abciximab: implications
for clinical practice. Nat. Rev. Cardiol. 7, 539
25 Hartman, G.D. et al. (1992) Non-peptide fibrinogen receptor
antagonists. 1. Discovery and design of exosite inhibitors. J. Med.
Chem. 35, 46404642
26 Cox, D. (2004) Oral GPIIb/IIIa antagonists: what went wrong? Curr.
Pharm. Des. 10, 15871596
27 Desgrosellier, J.S. and Cheresh, D.A. (2010) Integrins in cancer:
biological implications and therapeutic opportunities. Nat. Rev. Cancer
10, 922
28 Nakamura, I. et al. (2007) Involvement of alpha(v)beta3 integrins in
osteoclast function. J. Bone Miner. Metab. 25, 337344
29 Robinson, S.D. and Hodivala-Dilke, K.M. (2011) The role of beta3integrins in tumor angiogenesis: context is everything. Curr. Opin. Cell
Biol. 23, 630637
30 Wilder, R.L. (2002) Integrin alpha V beta 3 as a target for treatment of
rheumatoid arthritis and related rheumatic diseases. Ann. Rheum.
Dis. 61 (Suppl. 2), ii96ii99
31 Friedlander, M. et al. (1996) Involvement of integrins alpha v beta 3
and alpha v beta 5 in ocular neovascular diseases. Proc. Natl. Acad. Sci.
U.S.A. 93, 97649769
32 Hersey, P. et al. (2010) A randomized phase 2 study of etaracizumab, a
monoclonal antibody against integrin alpha(v)beta(3), + or
dacarbazine in patients with stage IV metastatic melanoma. Cancer
116, 15261534
33 Murphy, M.G. et al. (2005) Effect of L-000845704, an alphaVbeta3
integrin antagonist, on markers of bone turnover and bone mineral
density in postmenopausal osteoporotic women. J. Clin. Endocrinol.
Metab. 90, 20222028
34 Karpusas, M. et al. (2003) Crystal structure of the alpha1beta1 integrin
I domain in complex with an antibody Fab fragment. J. Mol. Biol. 327,
10311041
35 Hashmi, S. and Marinkovich, M.P. (2011) Molecular organization of the
basement membrane zone. Clin. Dermatol. 29, 398411
36 Giancotti, F.G. (2007) Targeting integrin beta4 for cancer and antiangiogenic therapy. Trends Pharmacol. Sci. 28, 506511
37 Kisker, O. (2008) Integrins: targets for anti-angiogenic therapy. In
Tumor Angiogenesis: Basic Mechanisms and Cancer Therapy (Marme,
D. and Fusenig, N.E., eds), pp. 761777, Springer
38 Mas-Moruno, C. et al. (2010) Cilengitide: the first anti-angiogenic small
molecule drug candidate design, synthesis and clinical evaluation.
Anticancer Agents Med. Chem. 10, 753768
39 Bell-McGuinn, K.M. et al. (2011) A phase II, single-arm study of the
anti-alpha5beta1 integrin antibody volociximab as monotherapy in
patients with platinum-resistant advanced epithelial ovarian or
primary peritoneal cancer. Gynecol. Oncol. 121, 273279
40 Almokadem, S. and Belani, C.P. (2012) Volociximab in cancer. Expert
Opin. Biol. Ther. 12, 251257
41 Barkan, D. and Chambers, A.F. (2011) Beta1-integrin: a potential
therapeutic target in the battle against cancer recurrence. Clin.
Cancer Res. 17, 72197223
42 Van Aarsen, L.A. et al. (2008) Antibody-mediated blockade of
integrin alpha v beta 6 inhibits tumor progression in vivo by a
transforming growth factor-beta-regulated mechanism. Cancer Res.
68, 561570
43 Rosenthal, M.A. et al. (2010) Evaluation of the safety, pharmacokinetics
and treatment effects of an alpha(v)beta(3) integrin inhibitor on bone
turnover and disease activity in men with hormone-refractory prostate
cancer and bone metastases. Asia Pac. J. Clin. Oncol. 6, 4248
44 Reardon, D.A. et al. (2011) Cilengitide: an RGD pentapeptide
alphavbeta3 and alphavbeta5 integrin inhibitor in development for
glioblastoma and other malignancies. Future Oncol. 7, 339354
45 Friess, H. et al. (2006) A randomized multi-center phase II trial of the
angiogenesis inhibitor Cilengitide (EMD 121974) and gemcitabine

Trends in Pharmacological Sciences July 2012, Vol. 33, No. 7

46

47

48

49
50

51
52

53

54

55
56
57

58

59

60

61

62

63
64

65

66

67

68

compared with gemcitabine alone in advanced unresectable

pancreatic cancer. BMC Cancer 6, 285
Kim, K.B. et al. (2007) A randomized phase II study of EMD 121974 in
patients (pts) with metastatic melanoma (MM). J. Clin. Oncol. 25
(Suppl. 18S), Abstract 8548
Nabors, L.B. et al. (2007) Phase I and correlative biology study of
cilengitide in patients with recurrent malignant glioma. J. Clin. Oncol.
25, 16511657
Stupp, R. et al. (2010) Phase I/IIa study of cilengitide and temozolomide
with concomitant radiotherapy followed by cilengitide and
temozolomide maintenance therapy in patients with newly
diagnosed glioblastoma. J. Clin. Oncol. 28, 27122718
Tabatabai, G. et al. (2010) Targeting integrins in malignant glioma.
Target Oncol. 5, 175181
Stoeltzing, O. et al. (2003) Inhibition of integrin alpha5beta1 function
with a small peptide (ATN-161) plus continuous 5-FU infusion reduces
colorectal liver metastases and improves survival in mice. Int. J.
Cancer 104, 496503
Mitjans, F. et al. (2000) In vivo therapy of malignant melanoma by
means of antagonists of alpha v integrins. Int. J. Cancer 87, 716723
ODay, S. et al. (2011) A randomised, phase II study of intetumumab, an
anti-av-integrin mAb, alone and with dacarbazine in stage IV
melanoma. Br. J. Cancer 105, 346352
Wirth, M. et al. (2012) Final analysis: a multicenter phase I study of
EMD 525797 (DI17E6), a novel humanized monoclonal antibody to
human av integrins, in progressive castrate-resistant prostate cancer
with bone metastases after chemotherapy. J. Clin. Oncol. 30 (Suppl. 5),
Abstract 231
Schnell, O. et al. (2009) Imaging of integrin alphavbeta3 expression in
patients with malignant glioma by [18F]galacto-RGD positron emission
tomography. Neuro. Oncol. 11, 861870
Beer, A.J. and Schwaiger, M. (2011) PET imaging of alphavbeta3
expression in cancer patients. Methods Mol. Biol. 680, 183200
Schottelius, M. et al. (2009) Ligands for mapping alphavbeta3-integrin
expression in vivo. Acc. Chem. Res. 42, 969980
Barnes, J. et al. (2006) MicroSPECT imaging of tumor response with
the avb3 radiopharmaceutical 99mTc-NC100692. J. Nucl. Med.
Meeting Abstracts 47, 175P
Battle, M.R. et al. (2011) Monitoring tumor response to antiangiogenic
sunitinib therapy with 18F-fluciclatide, an 18F-labeled alphaVbeta3integrin and alphaV beta5-integrin imaging agent. J. Nucl. Med. 52,
424430
Taga, T. et al. (2002) Alpha v-integrin antagonist EMD 121974 induces
apoptosis in brain tumor cells growing on vitronectin and tenascin. Int.
J. Cancer 98, 690697
Mikkelsen, T. et al. (2009) Radiation sensitization of glioblastoma by
cilengitide has unanticipated schedule-dependency. Int. J. Cancer 124,
27192727
Coller, B.S. (1985) A new murine monoclonal antibody reports an
activation-dependent
change
in
the
conformation
and/or
microenvironment of the platelet glycoprotein IIb/IIIa complex. J.
Clin. Invest. 76, 101108
Scarborough, R.M. et al. (1993) Design of potent and specific integrin
antagonists. Peptide antagonists with high specificity for glycoprotein
IIb-IIIa. J. Biol. Chem. 268, 10661073
Sagi, K. et al. Ajinomoto Co. Inc. Novel phenylalanine derivatives,
WO2003070709
Tilg, H. and Kaser, A. (2010) Vedolizumab, a humanized mAb against
the alpha4beta7 integrin for the potential treatment of ulcerative
colitis and Crohns disease. Curr. Opin. Investig. Drugs. 11, 12951304
Giugliano, R.P. et al. (2000) First report of an intravenous and oral
glycoprotein IIb/IIIa inhibitor (RPR 109891) in patients with recent
acute coronary syndromes: results of the TIMI 15A and 15B trials. Am.
Heart J. 140, 8193
Smith, E.E. et al. (2006) Risk factors for stroke after acute coronary
syndromes in the Orbofiban in Patients with Unstable Coronary
Syndromes Thrombolysis In Myocardial Infarction (OPUS-TIMI)
16 study. Am. Heart J. 151, 338344
Diamant, Z. et al. (2005) Effect of a very late antigen-4 receptor
antagonist on allergen-induced airway responses and inflammation
in asthma. Clin. Exp. Allergy 35, 10801087
Koga, Y. and Kainoh, M. (2010) PP-065-15 Effect of an orally active
small molecule alpha4beta1/alpha4beta7 integrin antagonist, TRK-170,
411

Review
on experimental colitis in mice. Int. Immunol. Meeting Abstracts
22, iii138
69 Miller, D.H. et al. (2012) Firategrast for relapsing remitting multiple
sclerosis: a phase 2, randomised, double-blind, placebo-controlled trial.
Lancet Neurol. 11, 131139
70 Hijazi, Y. et al. (2006) Evaluation of the effect of multiple-dose
administration of R411, a dual alpha4beta1-alpha4beta7 integrin
antagonist on the major CYP isoform activities in healthy volunteers.
Eur. J. Clin. Pharmacol. 62, 8385

412

Trends in Pharmacological Sciences July 2012, Vol. 33, No. 7

71 Kapustay, P.M. et al. AIDS Research LLC. LFA-1 alpha-subunit

antibodies and methods of use, US 6,919.077 B2
72 Greenberg, H.E. et al. (2000) Antiplatelet effects of MK-852, a platelet
fibrinogen receptor antagonist, in healthy volunteers. J. Clin.
Pharmacol. 40, 496507
73 Mackel, J.M. et al. Allegro Pharmaceuticals, Inc. Compositions
and methods for inhibiting cellular adhesion or directing
diagnostic or therapeutic agents to RGD binding sites, PCT/
US2010/056277