Articles |
From the Department of Medicine, Brigham and Women's Hospital, Harvard Medical School, Boston, Mass (D.I.S., H.X., C.R., N.K.R.); Celltech Therapeutics Ltd, Slough, UK (S.O.); and Harvard-MIT Division of Health Sciences and Technology, Cambridge, Mass (C.R.).
Correspondence to Daniel I. Simon, MD, Cardiovascular Division PBB-A3, Brigham and Women's Hospital, 75 Francis St, Boston, MA 02115. E-mail disimon{at}bics.bwh.harvard.edu.
| Abstract |
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IIbß3,
CD41/CD61) reduces acute ischemic complications of coronary
angioplasty and clinical restenosis at 6 months. However, 7E3 mAb is
not selective for platelet IIb/IIIa but also cross-reacts with the
leukocyte integrin Mac-1 (
Mß2, CD11b/CD18) and the vitronectin
receptor (
vß3, CD51/CD61). Information regarding how this mAb may
affect other cells important in vascular repair is scant. Potential
interactions of c7E3 Fab with inflammatory (ie, monocytes and
neutrophils), vascular smooth muscle, and endothelial cells may
contribute to the in vivo actions of c7E3 Fab. In this study we
explored the binding of 7E3 to monocytic cells and the functional
effect of 7E3 and c7E3 Fab on Mac-1mediated adhesion to fibrinogen
(FGN) and intercellular adhesion molecule-1 (ICAM-1), ligands abundant
in the injured vessel wall. Flow cytometry demonstrated that 7E3 bound
to THP-1 monocytic cells and identified a subpopulation (
10%) of
Mac-1 that was qualitatively similar to that recognized by CBRM1/5, a
mAb directed to an activation-specific neoepitope present on a subset
of Mac-1 molecules. mAb 7E3 bound to K562 cells transfected with just
the
subunit (CD11b) of Mac-1 but not to nontransfected cells,
confirming a direct interaction between 7E3 and Mac-1. mAb 7E3 and c7E3
Fab blocked the adhesion of Mac-1bearing cells to FGN (80±11% and
78±9% inhibition, respectively) and ICAM-1 (62±14% and 62±17%).
Both 7E3 and c7E3 Fab significantly inhibited (70±6% and 62±26%)
soluble FGN binding to human peripheral blood monocytes. Thus, c7E3 Fab
cross-reacts with the CD11b subunit of Mac-1 and interrupts
cell-extracellular matrix and cell-cell adhesive interactions and may
thereby influence the recruitment of circulating monocytes to sites of
vessel injury. Given the recent evidence that adherent and infiltrating
monocyte number directly correlates with the extent of neointimal
hyperplasia, inhibition of Mac-1dependent adhesion and
IIb/IIIa-dependent function by c7E3 Fab may jointly contribute to the
regulation of vascular repair and to the sustained clinical benefits
observed with c7E3 Fab after angioplasty.
Key Words: integrins monocytes cellular adhesion restenosis monoclonal antibody
| Introduction |
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Receptors of the integrin family are an important class of cell
adhesion molecules that mediate cell-cell and cellextracellular
matrix interactions that are central to inflammation, wound healing,
and hemostasis.13 Since integrins share common
and ß
subunits and because there is a high degree of homology between subunit
families,14 it is not surprising that some mAbs bind to
more than one integrin. c7E3 Fab is not selective for platelet IIb/IIIa
(
IIbß3, CD41/CD61) but also cross-reacts with the vitronectin
receptor (
vß3, CD51/CD61),15 found on endothelial and
smooth muscle cells, and the integrin Mac-1 (
Mß2,
CD11b/CD18),16 found on monocytes and neutrophils.
Mac-1, a leukocyte integrin that is mobilized from intracellular storage pools in response to a variety of agonists, including ADP, C5a, fMLP, and phorbol esters,17 18 is capable of binding heterogeneous ligands including ICAM-1,19 fibrin(ogen),20 21 22 and factor X.23 The binding of Mac-1 to ICAM-1 and fibrin(ogen) results in the adhesion of neutrophils/monocytes to the endothelium and to sites of fibrin deposition, respectively. After binding to factor X, Mac-1 coordinates the activation of factor X independent of tissue factor and factor VII, culminating in rapid fibrin formation.23 mAbs to Mac-1 interrupt the adhesive and migratory capability of leukocytes and reduce tissue injury in models of inflammation.24 25 26 27
Circulating monocytes are among the earliest cells recruited to sites of vessel injury28 29 and have the potential to interact with other vascular cells by secreting growth factors and cytokines.30 31 32 In fact, adherent and infiltrating monocyte number directly correlates with the extent of neointimal hyperplasia after deep vessel injury.33 Our demonstration in this study that 7E3 and c7E3 Fab inhibit Mac-1mediated adhesion to FGN and ICAM-1 in vitro may provide an additional mechanism for the beneficial effects of this mAb therapy.
| Methods |
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M subunit of Mac-1 (CD11b) that blocks FGN binding to
Mac-1,35 was purchased from DAKO Corp. The stimulating
CD18 mAb KIM127 was a generous gift of Dr Martyn Robinson (Celltech
Ltd, Slough, England).36 Additional Mac-1 mAbs included
TS1/18, a mAb to the common ß2 subunit (CD18) of Mac-1, and CBRM1/5,
a mAb to an activation-specific neoepitope in a subpopulation of Mac-1
molecules (kindly provided by Dr Timothy A. Springer, Harvard Medical
School, Boston, Mass).37 mAbs 7E3 and 10E5,38
murine mAbs to glycoprotein IIb and/or IIIa that block platelet FGN
binding, and c7E3 Fab,39 a Fab fragment of a human-mouse
genetic reconstruction of murine 7E3, in which mouse heavy and light
chain variable regions were linked to the constant domains of a human
IgG1 heavy chain and
light chain, respectively, were kindly
provided by Dr Barry S. Coller (Mt Sinai Medical Center, New York, NY).
Soluble human ICAM-1/Ig, a recombinant fusion protein comprising the
extracellular domain of human ICAM-1 linked to the constant region of
human IgG1, was obtained from Chiron Corp. FITC-conjugated goat
anti-mouse IgG, F(ab')2 antibody was obtained from
Boehringer Mannheim Corp.
Cell Transfection
Erythroleukemic K562 cells (European Collection of Animal Cell
Cultures) were transfected with the
M (CD11b) subunit of Mac-1 as
previously described.40 The CD11b gene was cloned by PCR
amplification from first-strand cDNA prepared from U937 cells
stimulated with 10 ng/mL phorbol myristate acetate for 48 hours. The
gene was cloned into the expression vector EE6 hCMV carrying a
G418-resistance marker for expression in K562 cells. This plasmid was
linearized by using Sal I and then 40 µg of linearized DNA
was transfected into 107 K562 cells by electroporation,
using a BioRad Gene Pulser unit. Cells and DNA were subjected to one
pulse at 250 V with a capacitance of 900 µF.
CHO cells transfected with human Mac-1 (CD11b/CD18) or the closely
related leukocyte integrin p150,95 (CD11c/CD18) were provided by Dr
Timothy A. Springer.35 Briefly,
M (CD11b) or
X
(CD11c) and ß2 (CD18) subunits of Mac-1 in pCDM8 were cotransfected
by electroporation with the pDCHIP plasmid, containing a CHO
dihydrofolate reductase minigene, into CHO DG44 cells. Cells were
selected with methotrexate, and a homogeneous population of positively
expressing cells was obtained by immunopanning. Expression was then
augmented by increasing the concentration of methotrexate (0.05 to
0.2 µmol/L) in culture. Both types of transfected cells, but not
the nontransfected DG44 cells, acquired the ability to bind soluble
125I-labeled FGN. Furthermore, Mac-1 and p150,95
transfectants bound equivalent amounts of 125I-FGN,
confirming equivalent expression of functional protein.
Cell Lines and Culture Conditions
The monocytic THP-1 cell line (American Type Culture Collection)
was maintained in RPMI 1640 and supplemented with 10% (vol/vol) FBS.
Unless otherwise indicated, medium containing 20 mmol/L HEPES,
2 mmol/L L-glutamine, 100 U/mL penicillin, and 100
µg/mL streptomycin was used in all cases. Differentiation of
monocytic cells (106 per milliliter), which is accompanied
by increased expression of Mac-1, was induced by treatment with 1 ng/mL
TGF-ß1 and 50 nmol/L 1,2-(OH)2 vitamin D3 for
24 hours.41 K562 cells were cultured in DMEM supplemented
with 10% FBS; CD11b K562 cells were cultured in DMEM containing G418
(1 mg/mL) and 10% FBS. Mac-1 and p150,95 CHO cells were cultured in
-MEM supplemented with 10% heat-inactivated, dialyzed FBS, 0.1
µmol/L methotrexate, and 10 µmol/L thymidine. Incubations were
performed at 37°C, 5% CO2. Peripheral blood mononuclear
cells were isolated from 10% (vol/vol) CPD-anticoagulated human blood
by Ficoll-Hypaque centrifugation42 and human monocytes
were separated from peripheral blood mononuclear cells by adherence to
human AB serum-coated plastic Petri dishes. Monocytes were maintained
in RPMI 1640 supplemented to 10% (vol/vol) with human AB serum.
Adhesion Assays
Adherent cells were assayed by a colorimetric method, as
previously described.43 44 Cytokine-primed monocytic THP-1
cells or Mac-1transfected CHO cells were activated with ADP (10
µmol/L), fMLP (1 µmol/L), or the Mac-1activating mAb KIM 127
(10 µg/mL). Activated cells were then added to wells precoated with
the Mac-1 ligands FGN (100 µg/mL) or ICAM-1 (10 µg/mL) and blocked
with gelatin. Cells (105 per well) were resuspended in
serum-free RPMI containing 0.5% BSA at 106 per milliliter
and were incubated in the presence or absence of the indicated mAbs
(intact 7E3, c7E3 Fab, 10E5 [anti-IIb/IIIa, noncross-reacting with
Mac-1],45 and LPM19c [anti-CD11b]) at a concentration
of 1 to 20 µg/mL and placed in 96-well microtiter plates for 1 to 2
hours at 37°C. Plates were washed with 0.9% NaCl three times, and
adherent cells were fixed in methanol for 15 minutes, stained with
Giemsa, and adhesion-quantified by measuring absorbance at 540 nm. Data
are expressed as percent of maximum adherent responses of respective
sets of treatment.
Flow Cytometry
K562 or THP-1 cells (2.5x106 per milliliter) were
washed and resuspended in 200 µL of RPMI containing 2.5% BSA. Fc
receptors were blocked by addition of human serum at a final
concentration of 1%. The primary mAb was then added to the cell
suspension followed by incubation on ice for 30 minutes. Cells were
treated with ADP (10 µmol/L) or fMLP (1 µmol/L) for 15
minutes at 37°C before incubation with the primary mAb. After
washing, cells were resuspended in 200 µL of the same medium
containing FITC-conjugated goat anti-mouse F(ab')2
fragments and incubated for 30 minutes on ice. Flow cytometry was
performed on a Becton Dickinson FACScan (Becton Dickinson
Immunocytometry Systems). Excitation wavelength was set at 488 nm and
emission at 550 nm. Nonspecific fluorescence was determined on cells
incubated in the absence of the primary mAb.
Fibrinogen Binding Assay
The binding of soluble FGN to human peripheral blood monocytes
was investigated as previously described by Altieri and
coworkers20 with modification. 125I-labeled
FGN (1.0 µmol/L) was added to ADP-stimulated human monocytes
(105) adherent to microtiter wells for 60 minutes at
25°C. Cell-free FGN was removed by washing the adherent human
monocytes, and cell-bound FGN was determined by counting an aliquot of
the cell lysate. Specific binding was calculated by subtracting the
counts obtained in the presence of a 20-fold excess of unlabeled FGN
from total binding. The effect of mAbs was determined by preincubating
ADP-stimulated monocytes for 30 minutes before the addition of
125I-FGN.
| Results |
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M subunit (CD11b) of Mac-1 that also blocks
adhesion to FGN and ICAM-1,35 recognizes total Mac-1
expressed. In accordance with the findings of Diamond and
Springer37 with neutrophils and monocytes, CBRM1/5 bound
to fMLP activated THP-1 cells at a significantly lower level than
LPM19c (mean fluorescence 49 versus 207; Fig 1A
|
To determine whether 7E3 bound directly to Mac-1 on monocytic cells, we
used erythroleukemic K562 cells, which do not express Mac-1 and are
capable of being stably transfected.40 7E3 bound to K562
cells transfected with the
subunit (CD11b) of Mac-1 but not to
nontransfected cells, supporting a direct interaction between 7E3 and
Mac-1 (Fig 1B
).
7E3 and c7E3 Fab Antibodies Inhibit Mac-1Mediated Adhesion to FGN
and ICAM-1
The functional relevance of 7E3's cross-reaction with Mac-1 was
investigated by exploring the effect of 7E3 or c7E3 Fab on cellular
adhesion to FGN and ICAM-1. The agonist fMLP increased adhesion of
monocytic THP-1 cells to FGN-coated wells >10-fold (Fig 2A
and 2B
). LPM19c, an anti-CD11b mAb that blocks FGN binding
to Mac-1,35 inhibited FGN adhesion by 82%
(P<.01), indicating that THP-1 cell adhesion is Mac-1
dependent. 7E3 and c7E3 Fab blocked adhesion to FGN by 80% and 78%
(P<.01), respectively. 10E5, an anti-IIb/IIIa mAb that does
not cross-react with Mac-1,45 had minimal effect. A dose
response for the inhibition of monocytic cell adhesion by 7E3 is
depicted (Fig 2C
), indicating that the IC50 is
10
µg/mL.
|
To confirm the ability of 7E3 to inhibit Mac-1 function and establish
that inhibition by 7E3 or c7E3 Fab required Mac-1 expression, we also
investigated CHO cells transfected with human Mac-1. CHO cells, which
are devoid of Fc receptors, were selected for these experiments because
our soluble ICAM-1 preparation is a recombinant fusion protein
comprising the extracellular domain of ICAM-1 linked to the constant
region of human IgG1. Mac-1 CHO cells adhered to FGN after activation
with the KIM 127 mAb (Fig 3
). Adhesion by Mac-1 CHO
cells was inhibited by LPM19c (95±2% inhibition), confirming the role
of Mac-1 in this adhesive pathway. Further evidence that Mac-1
expression is necessary to promote the adhesion of CHO cells to FGN is
supported by lack of demonstrable adhesion, under these conditions, of
nontransfected DG44 CHO cells (data not shown) and CHO cells
transfected with a distinct but closely related ß2 integrin, p150,95
(CD11c/CD18) (Fig 3
). While p150,95 has been shown to mediate adhesion
of fMLP-activated neutrophils48 and phorbol
esteractivated B lymphocytes49 to FGN-coated surfaces,
we were unable to demonstrate significant adhesion of KIM
127stimulated p150,95 CHO cells to FGN in this experimental system.
This lack of adhesion of p150,95 CHO cells may reflect
cell-typespecific differences (transfected versus nontransfected
cells) or different activation requirements in transfected cells.
|
We next tested whether 7E3 would inhibit Mac-1 binding to ICAM-1, an
adhesion molecule that facilitates the adhesion of monocytes and
neutrophils to the endothelium.19 KIM 127 stimulated
adhesion of Mac-1 CHO cells to ICAM-1 (Fig 4A
and 4B
).
LPM19c blocked adhesion to ICAM-1 by 86% (P<.01),
indicating that transfected CHO cell adhesion to ICAM-1 is Mac-1
dependent. 7E3 and c7E3 Fab reduced adhesion to ICAM-1 by 62% and
63%, respectively (P<.05), while 10E5 had no effect.
|
7E3 and c7E3 Fab Antibodies Inhibit Mac-1Mediated
Soluble FGN Binding by Human Peripheral Blood Monocytes
To further evaluate the functional relevance of the interaction
between 7E3 and Mac-1, we investigated whether 7E3 and c7E3 Fab are
capable of modulating Mac-1 function in freshly isolated human
peripheral blood monocytes. ADP-stimulated human monocytes bound
soluble FGN (
175 000 FGN molecules per cell). LPM19c inhibited FGN
binding to human monocytes by 93% (Table
), confirming
that FGN binding to human monocytes is Mac-1 dependent. Both 7E3 and
c7E3 Fab significantly inhibited soluble FGN binding to human
peripheral blood monocytes. Lack of inhibition of FGN binding by 10E5,
an anti-IIb/IIIa mAb that blocks FGN binding to IIb/IIIa but not to
Mac-1,45 not only confirms the specificity of 7E3 but also
suggests that platelet contamination of peripheral blood monocytes is
unlikely to account for soluble FGN binding to human monocytes.
|
| Discussion |
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subunit of the leukocyte integrins LFA-1 (CD11a),
Mac-1 (CD11b), and p150,95 (CD11c).51 Altieri and
Edgington16 have previously shown that 7E3 cross-reacts
with monocyte Mac-1, recognizing an activation-dependent neoepitope
induced by agonists such as ADP and fMLP, which induce transients in
cytosolic Ca2+. However, reports that 7E3 cross-reacts with
Mac-1 have been cautiously interpreted owing to concerns about
potential platelet contamination.39 We have addressed this
concern by using a monocytic cell line and cells transfected with human
Mac-1. 7E3 bound to K562 cells transfected with the
subunit (CD11b)
of Mac-1 but not to nontransfected cells, supporting a direct
interaction between 7E3 and Mac-1. The demonstration of 7E3 binding to
purified ligand binding or I domain of CD11b reported previously by
Zhou and colleagues52 provides additional compelling
evidence for a direct interaction between 7E3 and Mac-1. These prior
studies have explored the functional consequence of the cross-reaction
of 7E3 with Mac-1 by examining soluble ligand (ie, factor X) binding,
which was largely inhibited by 7E3 (75% to 88%).16 The
current study now shows that 7E3 blocks Mac-1dependent adhesion to
fibrin(ogen) and ICAM-1, ligands abundant in the acutely injured vessel
wall.53 A dose response for the inhibition of monocytic
cell adhesion by 7E3 demonstrated an IC50 of
10 µg/mL
(67 nmol/L). This is in close agreement with the reported
Kd (
150 nmol/L) of 7E3 for binding to
Mac-1bearing monocytes.16 It is important to note that
7E3 apparently binds to Mac-1 with lower affinity than IIb/IIIa
(Kd, 3.4 nmol/L).38 Pharmacokinetic
data indicate that bolus infusion of c7E3 Fab in cynomolgus monkeys
resulted in a peak plasma concentration of
2.5 µg/mL (54 nmol/L,
assuming molecular weight of c7E3 Fab of 48 kD).39 Thus,
the relative importance of 7E3-mediated inhibition of IIb/IIIa versus
Mac-1 in vivo is currently unknown.
The avidity of integrins may be rapidly and reversibly altered from a
latent ("inactive") state to a high-affinity ("active")
state without changes in receptor number. Receptor activation, most
likely secondary to conformational change(s), increases ligand affinity
of ß1,54 ß2,36 and ß355
integrins. For example, agonist stimulation of platelets induces
fibrinogen binding to activated IIb/IIIa that is blocked by mAb
7E3.38 Coller and coworkers38 have
demonstrated that 7E3 recognizes an activation-dependent change in the
conformation of IIb/IIIa, because resting platelets bind 7E3 more
slowly than stimulated platelets. In the case of Mac-1, specific
agonists (eg, ADP, fMLP) stimulating mAbs (eg, KIM 127 and
185)36 56 and Mn2+57 are capable
of directly activating Mac-1 from a low- to high-affinity
ligand-binding state by inducing Ca2+ transients or by
binding to the ß2 subunit or divalent-cation domains of the
M
subunit, respectively. Analagous to the interaction between 7E3 and
platelet IIb/IIIa, CBRM1/5 is directed to an activation-specific
epitope on leukocyte Mac-1 and is capable of completely blocking
Mac-1dependent adhesion.37 Our data suggest the
possibility that 7E3 also binds to activated Mac-1. 7E3 bound to CD11b
K562 cells but not nontransfected K562 cells and identified a
subpopulation of Mac-1 by flow cytometry that is qualitatively similar
to the subpopulation identified by CBRM1/5. However, these mAbs
apparently recognize distinct activation epitopes, because c7E3 Fab, a
humanized Fab fragment of intact 7E3, failed to block CBRM1/5 binding
as assessed by flow cytometry.
The early response to vascular injury is characterized by migration of platelets and inflammatory cells, including monocytes, to the injured vessel wall.58 59 Therefore, the ability of 7E3 to inhibit not only IIb/IIIa-mediated platelet aggregation but also Mac-1mediated monocyte adhesion may contribute to the process of vessel wall passivation observed clinically in the EPIC Trial. Among the earliest cells recruited into experimental vascular lesions induced in animals and spontaneous atherosclerosis in human arteries,28 29 monocytes serve as markers, initiators, and promoters of vascular injury. Balloon injury of the vessel wall is associated with a marked increase in the expression and secretion of monocyte chemoattractant protein-1.60 Pathological examination of human arteries and saphenous veins after angioplasty or stent placement has revealed monocytes adherent to and within vessel walls.61 There is emerging evidence implicating infiltrating monocytes in the pathogenesis of neointimal hyperplasia after mechanical arterial injury. The activation status of circulating monocytes62 and expression of Mac-163 at the time of angioplasty have been reported to predict later restenosis, and recently, Rogers and coworkers33 have demonstrated that the number of adherent and infiltrating monocytes exquisitely correlated with the extent of neointimal thickening and proliferation after arterial injury. Libby and coworkers7 have proposed a cascade model for restenosis, in which local inflammatory activation of endothelial cells, smooth muscle cells, and leukocytes occurs in a predictable sequence driven by ongoing autocrine and paracrine signals that persist after the original injury and contribute to later phases of intimal thickening. The precise mechanisms underlying the linkage between monocyte adhesion/infiltration and neointimal hyperplasia in this cascade model remain to be elucidated but may involve the elaboration of cytokines and growth factors chemotactic and mitogenic for smooth muscle cells.30 31 32
Therefore, we speculate that the cross-reaction of 7E3 or c7E3 Fab with
Mac-1 may play an additional role in inducing passivity of the vessel
wall by two mechanisms: (1) blocking the adhesion of monocytes to
ICAM-1 and fibrin(ogen) and (2) decreasing thrombus deposition at the
site of arterial injury by inhibiting the binding of factor X and its
activation to factor Xa, as previously shown by Altieri and
coworkers.23 Other platelet IIb/IIIa receptor inhibitors
under active clinical investigation (ie, lamifiban, tirofiban, and
xemlofiban) have varying degrees of specificity with the target (ie,
IIb/IIIa) and homologous (ie,
vß3, Mac-1)
integrins.64 The clinical relevance of variable IIb/IIIa,
Mac-1, and
vß3 blockade and its resultant effects on acute
ischemic complications and restenosis after percutaneous
transluminal coronary angiography remain to be determined.
| Selected Abbreviations and Acronyms |
|---|
|
| Acknowledgments |
|---|
Received September 30, 1996; accepted December 3, 1996.
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