Drug – bio-affecting and body treating compositions – In vivo diagnosis or in vivo testing
Reexamination Certificate
1999-10-22
2003-08-26
Jones, Dameron L. (Department: 1616)
Drug, bio-affecting and body treating compositions
In vivo diagnosis or in vivo testing
C424S001110, C424S001650, C424S001690
Reexamination Certificate
active
06610269
ABSTRACT:
This invention relates to diagnostic imaging techniques in which a disease state may be imaged using a targeted contrast agent and to targeted contrast agents suitable for use in such techniques. More particularly the invention relates to the use of such contrast agents in which the targeting vector binds to receptors associated with angiogenesis. Such contrast agents may thus be used for diagnosis of for example malignant diseases, heart diseases, inflammation-related diseases, rheumatoid arthritis and Kaposi's sarcoma. Moreover such agents may be used in therapeutic treatment of these diseases.
New blood vessels can be formed by two different mechanisms: vasculogenesis or angiogenesis. Angiogenesis is the formation of new blood vessels by branching from existing vessels. The primary stimulus for this process may be inadequate supply of nutrients and oxygen (hypoxia) to cells in a tissue. The cells may respond by secreting angiogenic factors, of which there are many; one example, which is frequently referred to, is vascular endothelial growth factor (VEGF). These factors initiate the secretion of proteolytic enzymes which break down the proteins of the basement membrane, as well as inhibitors which limit the action of these potentially harmful enzymes. The other prominent effect of angiogenic factors is to cause endothelial cells to migrate and divide. Endothelial cells which are attached to the basement membrane, which forms a continuous sheet around blood vessels on the contralumenal side, do not undergo mitosis. The combined effect of loss of attachment and signals from the receptors for angiogenic factors is to cause the endothelial cells to move, multiply, and rearrange themselves, and finally to synthesise a basement membrane around the new vessels.
Angiogenesis is prominent in the growth and remodeling of tissues, including wound healing and inflammatory processes. Tumors must initiate angiogenesis when they reach millimeter size in order to keep up their rate of growth. As angiogenesis is accompanied by characteristic changes in the endothelial cells and their environment, this process is a promising target for therapeutic intervention. Inhibition of angiogenesis is also considered to be a promising strategy for antitumor therapy. The transformations accompanying angiogenesis are also very promising for diagnosis, an obvious example being malignant disease, but the concept also shows great promise in inflammation and a variety of inflammation-related diseases, including atherosclerosis, the macrophages of early atherosclerotic lesions being potential sources of angiogenic factors. These factors are also involved in re-vascularisation of infarcted parts of the myocardium, which occurs if a stenosis is released within a short time.
Angiogenesis involves receptors which are unique to endothelial cells. The surface of these cells is remodelled in preparation for migration, and cryptic structures are exposed where the basement membrane is degraded, in addition to the variety of-proteins which are involved in effecting and controlling proteolysis. A number of known receptors/targets associated with angiogenesis are listed in Table 1 below. In the case of tumors, the resulting network of blood vessels is usually disorganised, with the formation of sharp kinks and also arteriovenous shunts. Using the targeting principles described in the present disclosure, angiogenesis may be detected by the majority of the imaging modalities in use in medicine.
TABLE 1
Receptors/targets associated with angiogenesis
Receptors/Targets
&agr;
2
-antiplasmin
basement membrane components
basic fibroblast growth factor (bFGF)
biglycan (dermatan sulfate proteoglycan)
cartilage-derived inhibitor [inhibitor]
CD34
collagen type I, IV, VI, VIII
decorin (dermatan sulfate proteoglycan)
dermatan sulfate proteoglycans
endoglin
endosialin
endothelin
epidermal growth factor (heparin-binding)
fibrin
fibrinopeptide B
fibroblast growth factor, FGF-3, basic
fibronectin
Flt-1/KDR, Flt-4 (VEGF receptor)
FLT-1 (fms-like tyrosine kinase) (VEGF-A receptor)
heparan sulfate
hepatocyte growth factor
hepatocyte growth factor receptor (c-met)
hyaluronan
insulin-like growth factor
insulin-like growth factor/mannose-6-phosphate receptor
integrins: &bgr;
3
and &bgr;
5
, integrin &agr;
v
&bgr;
3
, integrin &agr;
6
&bgr;
1
(laminin
receptor), integrin &agr;
6
, integrin &bgr;
1
, integrin &agr;
2
&bgr;
1
,
integrin &agr;
5
(subunit of the fibronectin
receptor), integrin &agr;
v
&bgr;
5
, fibrin receptors
interferon-&agr;, &bgr; [inhibitors]
interleukins: IL-8, IL-12 [inhibitor]
Jagged gene product.
laminin
laminin fragments
leukemia inhibitory factor
Ly-6 (a lymphocyte activation protein)
matrix metalloprotease-2
metalloproteinases
metalloproteinase inhibitors
MHC class II
Notch gene product
placental growth factor
placental proliferin-related protein
plasminogen
plasminogen activator
plasminogen activator inhibitor-1
plasminogen activator receptor
platelet-derived growth factor (e.g. type BB)
platelet-derived endothelial cell growth factor
platelet factor 4 [inhibitor]
pleiotropin
proliferin, proliferin-related protein
receptor tyrosine kinases
selectins: E-selectin
SPARC
stress proteins (molecular charperones) (glucose
regulated, heat shock families)
syndecan
tissue inhibitor of metalloproteinases (e.g. TIMP-2)
thrombin
thrombin-receptor-activating tetradecapeptide
thrombospondin [inbibitor]
TIE receptors (tyrosine kinases with Ig- and EGF-like
domains)
tissue factor
transforming growth factor-&agr;, &bgr;
tumor growth factor-&agr;
tumor necrosis factor
urokinase-type plasminogen activator receptor
Vascular endothelial growth factor-A
Vascular endothelial growth factor-related protein
Vascular endothelial growth factor-A receptor
vitronectin
von Willebrand factor
note: many hormones, growth factors and other compounds which bind to cell surface receptors may act as vectors by binding to their receptors, or, when they are already bound to the cell surface, they are targets for vectors that bind to them, for instance antibodies.
As indicated above, many undesired conditions are associated with neovascularization or angiogenesis, the development or proliferation of new blood vessels. Examples of such conditions are listed in Table 2 below
TABLE 2
Diseases and indications associated with
angiogenesis
Diseases/Indications
arteriovenous malformations
astrocytomas
atherosclerosis
breast cancers
choriocarcinomas
colorectal cancers
gingivitis
glioblastomas
gliomas
hemangiomas (childhood, capillary)
hepatomas
hyperplastic endometrium
inflammation (e.g. chronic)
ischemic myocardium
Kaposi sarcoma
lung cancers
macular degeneration
melanoma
metastasis
neuroblastomas
occluding peripheral artery disease
osteoarthritis
ovarian cancers
pancreatic cancers
prostate cancers
psoriasis
retinopathy (diabetic, proliferative)
rheumatoid arthritis
scleroderma
seminomas
skin cancers
solid tumor formation
ulcerative colitis
The surface cells, endothelial cells, of such new blood vessels have greater than normal concentrations of various surface or transmembrane receptors, such as for example receptor tyrosine kinases (RTK), and it has been proposed to use radiolabelled or chromophore-labelled antibodies to such receptors, or similarly labelled analogues of natural protein ligands for such receptors, as a means of detecting centres of angiogenesis (see for example WO95/26364 (Orion), WO96/30046 (Genentech) and WO95/12414 (Repligen)).
Peptidic ligands however have relatively few attachment sites for detectable labels (reporters) and attachment of reporters at many sites on such peptidic ligands will affect the conformations which the ligand may adopt. A further problem with peptides is that they are often unstable in vivo.
There is therefore still a need for effective targeted contrast agents with affinities for receptors associated with angiogenesis.
The present invention addresses this need in two ways—firstly by providing targeted contrast agents based on non-peptidic ligands (vectors)—and se
Klaveness Jo
Naevestad Anne
Tolleshaug Helge
Amersham Health AS
Bacon & Thomas
Jones Dameron L.
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