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Advances in Brief |
Departments of Immunology and Molecular and Cell Biology and Research, ImClone Systems Incorporated, New York, New York 10014 [F. L., Y. L., W. O., R. B., A. S., J. O., A. H., D. J. H., P. B.]; Instituto di Ricerche Farmacologiche, Mario Negri, 20157 Milan, Italy [L. Z., E. D.]; and Departments of Surgery and Cell Biology, New York University School of Medicine, New York, New York 10016 [P. M.]
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ABSTRACT |
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 Top ABSTRACT IntroductionMaterials and MethodsResultsDiscussionREFERENCES |
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Introduction |
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TopABSTRACTIntroductionMaterials and MethodsResultsDiscussionREFERENCES |
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vß3 and
vß5 integrins; Ref.
4
) or pericellular protease activation systems
(plasminogen activator receptor; Ref. 5
) associated with
the vasculature. Many angiogenesis inhibitors are directed against less
specific (e.g., metalloproteinase inhibitors; Ref.
6
) or as yet undefined targets (e.g.,
angiostatin and endostatin; Refs. 7
and 8
).
It would appear, however, that the complex nature of the angiogenic
process and its regulation should provide an abundant source of
additional molecular targets. Our recent studies (9 , 10) aimed at developing angiogenesis inhibitors that target the VE-cad, an endothelial cell-specific cadherin localized at specialized cell-cell contact regions referred to as adherens junctions. Accumulating evidence implicates VE-cad in various aspects of vascular biology related to angiogenesis, including endothelial cell migration (9) and survival (11) , contact-induced growth inhibition (12) , vascular integrity (13) , and, most notably, endothelial cell assembly into tubular structures (14) . VE-cad-null mouse embryos exhibit severely impaired assembly of vascular structures, which results in embryonic lethality at day 9.5 (11) , implicating VE-cad as an important mediator in developmental angiogenesis. VE-cad represents one of the most endothelial cell-specific molecules. Its restricted distribution and unique biological function distinguish VE-cad as a potential target for endothelial cell-specific events, e.g., angiogenesis.
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Materials and Methods |
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TopABSTRACTIntroductionMaterials and MethodsResultsDiscussionREFERENCES |
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Anti-VE-cad Antibody.
The rat anti-VE-cad monoclonal antibody BV13 was developed and
characterized as described previously (13)
. The antibody
was purified from conditioned medium by protein G-Sepharose
chromatography. All antibody preparations used for animal studies,
including control rat IgG (Jackson ImmunoResearch Laboratories, West
Grove, PA), contained 
1.25 endotoxin units/ml endotoxin as
assessed by the Limulus Amebocyte Lysate assay kit
(BioWhittaker, Walkersville, MD).
In Vitro Angiogenesis Assays.
Capillary tube formation of 1G11 cells was performed in collagen
sandwich gels as described previously (17)
. In brief, type
I collagen from rat tail was diluted to a concentration of 1 mg/ml, and
the pH was neutralized by adding 0.1 volume of 10x MEM (Life
Technologies). Aliquots of collagen (250 µl) were added to each well
of 24-well plates and incubated at 37°C until solidified. 1G11 cells
were then seeded onto collagen-coated wells, and cell monolayers were
established by incubation for 24 h at 37°C. Unattached cells
were then aspirated, and overlying collagen gels were generated using
the same procedure as described above. For the tube assay performed in
the Matrigel system with bEND.3 cells, 2 x 104
cells were plated onto each well of a 24-well
plate coated with a layer of Matrigel (BD Biosciences, Bedford, MA) and
cultured for 24 h in MCDB133 medium (Life Technologies, Inc.).
Antibody BV13 was added to the collagen/Matrigel gels and culture
media, and the inhibitory effect on tube formation was assessed under a
Zeiss microscope.
In Vivo Angiogenesis Assays.
The mouse corneal micropocket assay was performed as described
previously (18)
using hydron-coated sucralfate pellets
containing 50 ng of bFGF (R&D Systems, Minneapolis, MN) or 200 ng of
VEGF165 with or without the addition of BV13 (1
µg). For systemic treatment, 50 µg of BV13 were administered to
mice i.p. twice weekly starting 24 h after pellet implantation.
Alginate tumor cell encapsulation and Matrigel plug assays were
performed as described previously (19)
. In both assays,
the antibodies were administered i.p. twice weekly at 25 or 50
µg/dose, and angiogenesis was quantitated by measuring the uptake of
FITC-dextran into plugs or beads. The Matrigel plugs were removed 21
days after implantation, quantitated, and processed for histological
examination as described previously (19)
.
Mouse Tumor Models.
Lewis lung tumors were established by injecting 2 x 106
D122 tumor cells s.c. into the right flank of
C57BL/6 mice. Twenty-four h later, mice received twice weekly i.p.
injections of various doses of BV13 or control IgG. Tumors were
measured twice weekly with calipers, and tumor volumes were calculated
using the formula [
/6 (w1 x w2 x w2)], where
w1 represents the largest tumor
diameter, and w2 represents the
smallest tumor diameter. For the pulmonary metastasis model, mice
received an intrafootpad injection of 1 x 105
D122-96 tumor cells (19)
. When
footpad tumors reached 5 mm in diameter, the tumor-bearing leg was
surgically ligated. Mice were then divided into three groups receiving
i.p. injections of either BV13 (25 and 50 µg/dose) or control IgG (50
µg/dose) twice weekly for 3 weeks. Mice were then sacrificed, and the
lungs were removed and weighed to measure the metastatic load, and
tumor nodules on the lung surface were also counted as described
previously (19)
.
Human Tumor Xenograft Model.
The s.c. human epidermoid (A431) tumors were established by injecting
2 x 106
tumor cells mixed in an
equal volume of Matrigel into athymic nude mice s.c. in the right
flank. Tumors were allowed to reach 150–200 mm3
in size, and then randomized groups of 10 animals received twice-weekly
i.p. injections of BV13 or control IgG (50 µg/dose). Tumors were
measured twice weekly with calipers, and tumor volumes were calculated
as described above.
Histology.
Six-µm sections of Matrigel plugs were stained with anti-von
Willebrand factor antibody (DAKO Corp., Carpinteria, CA) as described
previously (19)
. A431 tumors or lungs from mice bearing
lung metastases were fixed in 10% neutral buffered formalin overnight
at 4°C, embedded in paraffin or frozen with OCT and sectioned. All
paraffin-embedded tissue sections were stained with Mayer’s H&E
(Sigma). Anti-PECAM staining or terminal deoxynucleotidyl
transferase-mediated nick end labeling was performed as described
previously (19)
using In Situ Cell Death
Detection Kit (Boehringer Mannheim, Indianapolis, IN). Light and
fluorescent images of immunostained tissues were digitized with a Sony
camera and Scion CG-7 framegrabber and captured with NIH Image
Software.
Statistical Analysis.
Vessel density counts, tumor volume, and lung metastasis were analyzed
using the Student’s t test. Analyses were computed using
the statistical package in SigmaStat version 4.0 (Jandel Scientific,
San Rafael, CA).
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Results |
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To evaluate whether blocking VE-cad homophilic binding could inhibit
angiogenesis in vivo, we tested the effect of BV13 on
angiogenesis in three mouse models. In the mouse corneal micropocket
assay (18)
, hydron pellets containing 50 ng of bFGF and 1
µg of an irrelevant antibody (rat IgG1) induced a marked
neovascularization derived from the limbic vessels (Fig. 1
a, left panel). In contrast,
the eyes of animals receiving BV13-containing pellets (1 µg/pellet)
showed much fewer and thinner corneal capillaries (Fig. 1
a, right
panel) with a resulting 72% decrease in the vascular area (Fig. 1b)
. Similar results were obtained when BV13 was
administered locally in hydron pellets containing 200 ng of
VEGF165 or systemically (50 µg BV13/mouse,
twice weekly) in mice receiving implants with pellets containing 50 ng
of bFGF. VEGF-stimulated corneal angiogenesis was inhibited by 65%
with locally administered antibody, whereas bFGF-induced corneal
angiogenesis was inhibited by 47% with systemic antibody
administration (data not shown). To confirm the antiangiogenic effect
of BV13, we also tested this antibody in the Matrigel plug assay
(19)
. In this assay, extensive angiogenesis was induced by
s.c. injection of Matrigel supplemented with bFGF (500 ng) and
VEGF165 (10 µg). In contrast, plugs without
growth factors were virtually devoid of vessels. Two doses of BV13 (25
and 50 µg/dose) were chosen based on dose-response studies and the
results of previous studies (13)
. BV13 was administered to
mice by i.p. injection twice weekly for 21 days. Pharmacokinetic
studies were performed to determine a serum half-life of BV13 antibody
in mice of approximately 48 h.4
Treatment with
either dose of BV13 resulted in a >90% reduction of cellularity and
microvessel density in growth factor-supplemented plugs as compared
with control antibody (Fig. 2)
. Similar
results were obtained using an Alginate tumor cell encapsulation model
(Ref. 19
; data not shown). These results demonstrate that
BV13 has potent antiangiogenic activity in vivo.
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). In the A431 s.c. human
tumor xenograft model, tumor-bearing mice were treated i.p. with 50
µg of BV13 or control IgG twice weekly. BV13 significantly inhibited
A431 tumor growth relative to control antibody (75%;
P < 0.05; Fig. 3b
). Doses of BV13
lower than 50 µg had no significant effect on the growth of A431
tumors compared with control antibody. Histological examination of
tumors removed from animals after antibody treatment for various
periods of time (i.e., 2, 4, and 6 weeks) showed dramatic
differences between BV13- and control IgG-treated groups. Tumors from
animals receiving BV13 treatment for 2 weeks showed enhanced tumor
necrosis and markedly decreased vessel density (>80%;
P < 0.05; Fig. 3c
) as compared
with control IgG-treated mice. Double staining of tumors with
anti-PECAM antibody and terminal deoxynucleotidyl transferase-mediated
nick end labeling demonstrated endothelial cell apoptosis in the
vasculature of the BV13-treated A431 tumors (Fig. 3c)
as
well as increased tumor cell apoptosis. Analysis of sections at 4 or 6
weeks of BV13 treatment did not show a significant difference in
endothelial cell or tumor cell apoptosis from that observed at 2 weeks.
Interestingly, BV13-induced apoptosis was prominent only in the tumor
tissues, whereas similar treatment resulted in no observable apoptosis
in normal tissues such as lungs, hearts, and kidneys (data not shown).
This finding suggests that tumor vasculature is more susceptible to
BV13 treatment.
|
. Histological examination
showed that pulmonary metastasis was rarely detected as small nests of
tumor cells in the lungs of mice treated with 25 µg of BV13 (Fig. 4b)
. Several mice (7 of 10) treated with 50 µg of BV13 had
no evidence of micrometastases. These results suggest that in
addition to affecting the growth of a primary tumor, BV13 also inhibits
the growth of metastases. It is noteworthy that BV13 treatment affected
the formation of metastases much more strongly than primary tumor
growth. This finding suggests that it may be easier to inhibit the
neovascularization and growth of a very small tumor and/or
micrometastases with a VE-cad antibody, as compared with an
established tumor.
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Discussion |
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TopABSTRACTIntroductionMaterials and MethodsResultsDiscussionREFERENCES |
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vß3 (24)
antagonists.
It is important to note that BV13 has potent in vivo
antitumor activity at low doses (50 µg/dose). In contrast,
other potent antiangiogenic antibodies such as those that block the
functions of VEGF (25)
, VEGF receptor (19)
,
or vß3
(24)
must be given at 10-fold higher doses for comparable
effects. Because tumor growth was not completely inhibited by a 50 µg
dose of antibody, we attempted to increase dosing to achieve an even
better therapeutic result. However, higher doses of BV13 (>75 µg,
i.p.) resulted in increased vascular permeability and edema in the lung
followed by the death of some animals within 24–48 h. These findings
are similar to our previously reported results (13)
, where
we found that BV13 administered at doses 
50 µg by i.v.
injection resulted in increased vascular permeability, edema in the
lungs, and death of some animals. The slight difference in dose and
route of administration required to increase lung permeability is
likely due to differences in systemic uptake, peak serum levels, and
clearance of BV13 when administered by an i.p. versus an
i.v. route. Although not performed in these studies, our
pharmacokinetic studies with other rat antibodies in mice clearly show
a lower maximal antibody serum concentration when systemic
administration is via an i.p. route versus an i.v.
injection. The permeability effect of BV13 on normal tissues is not
entirely unexpected because VE-cad is equally expressed in tumor and
normal
vasculature.5
It
should also be noted that BV13 does not preferentially distribute to
tumor blood vessels; rather, it can bind to vessels in several tissues
(13)
.6
Therefore,
anti-VE-cad antibodies may not only prevent the formation of adherens
junctions in nascent vasculature ("junction formation") but may
also interfere with established adherens junctions and thus cause
increased permeability of the affected vasculature ("junction
disruption"). We hypothesize that the VE-cad molecules on the tumor
vasculature are more "susceptible" to a therapeutic dose of an
antibody due to its poor structural integrity and active angiogenesis.
Indeed, we did not observe increased permeability in the lung or other
tissues at the therapeutically efficacious dose of 50 µg, nor did we
observe other overt signs of toxicity during the course of treatment in
a large number of animals used in a variety of studies.
Our results indicate that antibody BV13 would not be an appropriate agent for therapeutic use due to its disrupting activity on existing adherens junctions. We thus aim at identifying a more desirable anti-VE-cad angiogenesis inhibitor that would only inhibit adherens junction formation during assembly of vascular tubes but would have a negligible effect on existing junctions of established vessels. Additional studies will determine whether antibodies can be identified that preferentially effect only endothelium undergoing angiogenesis. However, it seems reasonable to anticipate that such antibodies can be developed. VE-cad is a large, transmembrane protein with five extracellular domains that mediate the formation and maintenance of adherens junctions through homophilic interactions. Specific regions of the VE-cad molecule responsible for homophilic interactions and adherens junction formation have not yet been defined. However, assuming that VE-cad-mediated adhesion is as complex as that of other classical cadherins (26 , 27) , the formation of adherens junctions is likely to involve multiple adhesive contacts between the multiple domains along the extracellular region of VE-cad (28) . Thus, it may be possible to target regions of the VE-cad protein that are responsible for one or more steps in the formation of adherens junctions but are not accessible or influenced once adherens junctions have formed. Indeed, in preliminary work using screening assays that distinguish between junction formation and disruption, we have identified unique VE-cad antibodies that inhibit adherens junction formation but do not disrupt existing junctions. Detailed analysis of these antibodies in animal models and of the VE-cad epitopes that give rise to differentially acting antibodies may lead to the identification of antibodies with high therapeutic potential for antiangiogenic treatment.
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ACKNOWLEDGMENTS |
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FOOTNOTES |
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1 Supported in part by a NIH Small Business
Innovation and Research grant. 
2 To whom requests for reprints should be
addressed, at Department of Immunology, ImClone Systems Incorporated,
180 Varick Street, New York, NY 10014. Phone: (646) 638-5035; Fax:
(212) 645-2054; E-mail: danh{at}imclone.com
3 The abbreviations used are: VEGF, vascular
endothelial growth factor; Flk-1/KDR, fetal liver kinase 1/kinase
insert domain containing receptor; Flt-1, FMS-like tyrosine kinase 1;
VE-cad, vascular endothelial-cadherin; bFGF, basic fibroblast growth
factor; PECAM, platelet/endothelial cell adhesion molecule.
4 F. Liao and E. Dejana, unpublished
data.
5 E. Dejana and A. Hooper, unpublished data.
6 E. Dejana, unpublished data.
Received 8/21/00. Accepted 10/31/00.
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v integrins. Science (Washington DC), 270: 1500-1502, 1995.vß3 antagonists promote tumor regression by inducing apoptosis of angiogenic blood vessels. Cell, 79: 1157-1164, 1994.[Medline]
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