Drug – bio-affecting and body treating compositions – Immunoglobulin – antiserum – antibody – or antibody fragment,... – Structurally-modified antibody – immunoglobulin – or fragment...
Reexamination Certificate
1999-09-27
2001-07-24
Saunders, David (Department: 1644)
Drug, bio-affecting and body treating compositions
Immunoglobulin, antiserum, antibody, or antibody fragment,...
Structurally-modified antibody, immunoglobulin, or fragment...
C424S001490, C424S001690, C424S009100, C424S009340, C424S009400, C424S009600, C424S134100, C424S142100, C424S143100, C424S178100, C435S007210, C514S002600
Reexamination Certificate
active
06264949
ABSTRACT:
1. INTRODUCTION
The present invention relates to the use of molecules capable of specifically binding a human &bgr; PDGF receptor (&bgr; PDGFR) as diagnostic reagents for the minimally invasive assessment and detection of fibrosis. The present invention relates to methods and compositions for the screening for the diagnosis and/or prognosis of fibrosis. The present invention also relates to noninvasive methods for monitoring the effectiveness of treatment of fibrosis. Such fibrosis can include, but are not limited to, liver, lung, kidney, prostate and breast fibrosis.
2. BACKGROUND
2.1. The Progression of Fibrosis
Progressive fibrosis of liver, kidney, lungs, and other viscera often results in organ failure leading to death or the need for transplantation. These diseases affect millions in the United States and worldwide. For example, hepatic fibrosis is the leading non-malignant gastrointestinal cause of death in the United States. Moreover, it has been increasingly recognized that progression of fibrosis is the single most important determinant of morbidity and mortality in patients with chronic liver disease (Poynard, T. P. et al., 1997, Lancet 349:825-832).
Currently there is no alternative to direct biopsy of affected organs to assess the extent of fibrosis. For all tissues this involves either percutaneous or transbronchial biopsy, procedures whose risks include bleeding, perforation or death. Moreover, biopsy is contraindicated in patients with end-stage diseases in whom there are clotting abnormalities.
2.2. Hepatic Fibrosis
In all tissues, activation of resident mesenchymal cells is a key event in the development of fibrosis. In the kidney, this mesenchymal cell is represented by the mesangial cell (Border, W. A., 1994, Current Opinion in Nephrology Hypertension 3:54-58) and in the liver, the hepatic stellate cell (HSC, otherwise referred to as Ito cells, fat-storing cells, lipocytes) fulfills this role. Subsequent to acute or chronic liver damage, HSC undergo activation, a process characterized by the transformation of resting cells into proliferative, fibrogenic, and contractile myofibroblast-like cells. Activated HSC contribute to the tissue repair process, namely the reconstitution of an extracellular matrix (ECM) network necessary for tissue regeneration. In cases of acute/self-limited tissue damage these changes are self-limited and effective. In contrast, cases of persistent liver injury result in chronic inflammation and lead to the accumulation of ECM. The reasons for the chronicity are not clear, but could reflect the presence of mediators unique to chronic injury, or more likely, failure of compensatory mechanisms (i.e., downregulators of inflammation, or matrix protease activity) to keep pace with the ongoing fibrosis.
A cascade of events involving soluble stimuli, matrix-related changes, and altered gene expression results in the activation of HSC. Activation consists of early (“initiation”) and late (“perpetuation”) phases. Early activation appears to be provoked by at least two stimuli, rapid deposition of cellular fibronectin, and release of soluble stimuli by Kupffer cells (hepatic macrophages). The late phase of activation consists of at least five discrete phenotypic changes: (1) proliferation, (2) mitogenesis, (3) contractility, (4) release of proinflammatory cytokines, and (5) matrix protease release.
Activation and proliferation of HSC in liver injury is associated with de novo expression of many cytokine receptors, including epidermal growth factor (EGF-R), transforming growth factor (TGF) &bgr;-R types I, II, and III, endothelial receptor (ET-R), vascular endothelial growth factor (VEGF)-R, thrombin-R and platelet derived growth factor (PDGF)-R (Friedman, S. L., 1997, Journal of Gastroenterology 32:424-430; Ankoma-Sey, V. M. et al., 1998, Oncogene 17:115-121; Friedman, S. L., 1989, Journal of Clinical Investigation 84:1780-1785; Wong, L. G. et al., 1994, Journal of Clinical Investigation 94:1563-1569). Moreover, HSC activation is associated with the expression of several cytokines, growth factors and inflammatory mediators, including EGF, FGF, ET-1, insulin-like growth factor (IGF), thrombin, TGF &agr;, TGF &bgr;, hepatocyte growth factor (HGF), stem cell factor (SCF), and PDGF (Friedman, S. L., 1997, Journal of Gastroenterology 32:424-430). HSC activation is also associated with an increase in the production of extracellular matrix components, namely collagen types I, III, IV, V, VI, XIV, proteoglycans, and glycoproteins, including fibronectin, laminin, and tenascin. Furthermore, HSC activation is associated with the production of matrix proteases, including MMP-2, stromelysin-1 (transin), MMP-1 (interstitial collagenase), and MT-MMP (membrane type-matrix metalloproteinase), and protease inhibitors, including TIMP-1, TIMP-2, and PAI-1. Thus, the expression of several different factors are associated with HSC activation.
2.3. Diagnosis and Staging of Disease
While detection of markers of fibrotic disease may be useful for prognosis modalities in vitro, no reliable system currently exists for the detection of fibrosis in a patient—information which would be extremely important for staging disease and designing an appropriate clinical approach. In fact, the inability to diagnose and image fibrosis in vivo, continues to be a major obstacle to the successful treatment of cancer and inflammatory disorders. Current surgical practice commonly resorts to vision and palpation in combination with locally determined protocols dictating the extent of tissue resection. Thus, tissue removed during surgery includes not only tissue suspected by the surgeon of being fibrotic, but also includes an amount of healthy tissue taken because the precise fibrotic margins cannot be readily ascertained by the surgeon. Accordingly, there is a great need in the art for sensitive methods to reliably detect and localize metastases in vivo.
3. SUMMARY OF THE INVENTION
The present invention relates to a minimally invasive test for the diagnosis and prognosis of fibrotic disease. In accordance with the present invention, a labeled cytokine ligand which binds specifically to a receptor on mesenchymal cells is administered to a patient, the extent of binding is used as an indicator of the mass of mesenchymal cells and the extent of fibrosis and the rate of fibrogenesis. In accordance with the present invention, the labeled ligand may be administered orally or intravenously and followed by methods known in the art for in vivo scanning as described herein.
The present invention relates to methods for the diagnosis and imaging of fibrosis using labeled molecules that specifically bind a &bgr; PDGF receptor, particularly for detecting and imaging metastases in vivo. The present invention relates to methods and compositions for screening, diagnosis and prognosis of fibrosis. The present invention further relates to methods for monitoring the effectiveness of treatment of fibrosis and for drug development.
In a preferred embodiment of the invention, fibrosis in a subject are detected by: (a) administering labeled molecules which specifically bind &bgr; PDGFR; (b) permitting the labeled molecules to preferentially concentrate in one or more fibrotic lesions in the subject and unbound labeled molecule to be cleared to background level; (c) determining the background level; and (d) detecting the labeled molecule such that detection of labeled molecule above the background level indicates the presence of a fibrotic lesion.
In another preferred embodiment, the labeled molecule of the invention can be detected in a subject wherein the subject had been administered the labeled molecule at a sufficient time interval prior to detection to allow the labeled molecule to preferentially concentrate at fibrotic lesions.
In specific embodiments the labeled molecule is labeled anti-PDGF-&bgr; antibody or fragments containing the &bgr; PDGF binding domain or peptide mimetics of PDGF-&bgr;. In another specific embodiment, the labeled molecule is a peptide or derivative thereof that binds &bgr; PDGFR bu
DeCloux Amy
Mount Sinai School of Medicine of New York University
Pennie & Edmonds LLP
Saunders David
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