Drug – bio-affecting and body treating compositions – Radionuclide or intended radionuclide containing; adjuvant... – Attached to antibody or antibody fragment or immunoglobulin;...
Reexamination Certificate
1999-11-22
2002-04-23
Hartley, Michael G. (Department: 1619)
Drug, bio-affecting and body treating compositions
Radionuclide or intended radionuclide containing; adjuvant...
Attached to antibody or antibody fragment or immunoglobulin;...
C424S009340
Reexamination Certificate
active
06375925
ABSTRACT:
This application is a 371 of PCT/US96/18289, filed Nov. 8, 1996.
FIELD OF THE INVENTION
This invention relates to the diagnosis of atherosclerosis. Specifically, the invention relates to methods and reagents for imaging atherosclerotic plaque in vivo.
HISTORY OF THE INVENTION
Clinical diagnosis of atherosclerosis is typically based (together with patient history and physical examination) on the results of an invasive diagnostic procedure such as angiography. A major impediment to the development of non-invasive diagnostic methods for atherosclerosis has been the lack of reagents and techniques which can distinguish plaque from components of normal vessel walls and blood. Reagents which have been investigated for binding to atherosclerotic plaque components include radiolabeled lipoprotein (LDL), apolipoprotein B (apo B), autologous platelets, antifibrin antibodies and components related to smooth muscle cell proliferation. In general, however, such agents have suffered from a lack of specificity and their detection in vivo has been complicated by substantial residual background signal which interferes with resolution of the target image.
SUMMARY OF THE INVENTION
The invention provides reagents and methods for their use in in vivo diagnosis of atherosclerosis. In particular, the invention provides monoclonal antibodies which bind oxidation-specific epitopes of oxidized LDL in vivo in atherosclerotic plaque lesions with high binding specificity. In addition, the invention provides a method for substantially reducing interference from background signal in the blood pool into which such agents are introduced for detection and quantification of atherosclerotic plaque burden.
An example of the monoclonal antibodies provided by the invention is MDA2, a murine IgGl&agr; antibody which has been discovered to have unpredictably high binding specificity in vivo for malondialdehyde (MDA)-lysine epitopes on oxLDL (particularly in the oxLDL-rich apoB component of atherosclerotic plaque). According to the diagnostic method of the invention, detectably labeled MDA2 monoclonal antibodies or Fab fragments thereof are introduced into the bloodstream of a patient. Detection of MDA2 bound to an atherosclerotic plaque lesion may be made by any method appropriate to the label applied to MDA2, but use of gamma and positron emitters for ease of signal detection and quantification of plaque burden based thereon is preferred.
MDA2 is taken up by atherosclerotic plaque at a rate of up to about 20 times higher than its rate of uptake by adjacent arterial tissue, where no detectable binding of MDA2 is found. MDA2 does not bind unoxidized LDL. A particular advantage of the invention is that by targeting the oxLDL-rich regions of atherosclerotic plaque, “hot spots” in plaque believed to be clinically relevant markers for unstable plaque lesions may be clearly imaged by detection of MDA2 binding in such lesions.
A further example of the monoclonal antibodies of the invention is NA59, a murine IgGl&agr; antibody which has also been discovered to have unusually high binding specificity in vivo for atherosclerotic plaque, in particular for 4-hydroxynonenal (4-HNE)-lysine epitopes in oxLDL. The NA59 mAb and Fab fragments thereof are taken up by atherosclerotic plaque at rates similar to MDA2 and are suitable for use as an in vivo diagnostic agent in the same manner described with respect to MDA2.
According to the diagnostic method of the invention, detectably labeled oxidation-specific antibodies such as MDA2 or NA59 are introduced into the bloodstream of the patient. To clear residual background signal, MDA or 4-HNE antigen (preferably joined to a carrier such as albumin or LDL) is also introduced into the bloodstream of the patient. On injection of the modified antigen, unbound MDA2 levels in circulation decline rapidly and most of the background signal is eliminated.
Binding of the monoclonal antibodies of the invention to oxLDL epitopes in atherosclerotic plaque is detected as noted above. The percent of the injected dose of either antibody taken up by plaque in vivo correlates strongly with the amount of plaque present in the imaged tissue, which may be estimated from the results of the inventive diagnostic assay.
REFERENCES:
patent: 5364612 (1994-11-01), Goldenberg
patent: WO91/02252 (1991-02-01), None
Palinski et al., “Antisera and monoclonal antibodies specific for epitopes generated during oxidative modificationof low density lipoprotein,” Arteriosclerosis 10:325-335, May 1990.
Curtis Linda K.
Palinski Wulf
Tsimikas Sotorios
Witztum Joseph L.
Foley & Lardner
Hartley Michael G.
The Regents of the University of California
LandOfFree
Methods and reagents for non-invasive imaging of... does not yet have a rating. At this time, there are no reviews or comments for this patent.
If you have personal experience with Methods and reagents for non-invasive imaging of..., we encourage you to share that experience with our LandOfFree.com community. Your opinion is very important and Methods and reagents for non-invasive imaging of... will most certainly appreciate the feedback.
Profile ID: LFUS-PAI-O-2911018