Chemistry: molecular biology and microbiology – Measuring or testing process involving enzymes or... – Involving antigen-antibody binding – specific binding protein...
Reexamination Certificate
1997-08-07
2001-05-01
Caputa, Anthony C. (Department: 1642)
Chemistry: molecular biology and microbiology
Measuring or testing process involving enzymes or...
Involving antigen-antibody binding, specific binding protein...
C435S007940, C435S011000, C424S130100, C424S001210, C530S387100
Reexamination Certificate
active
06225070
ABSTRACT:
FIELD OF THE INVENTION
The invention relates to monoclonal antibodies with binding specificity for oxidation-specific epitopes on lipoproteins in blood, coronary tissue and vascular tissue, including atherosclerotic plaque on such tissue. The invention further relates to methods for use of the monoclonal antibodies in detecting, monitoring and inhibiting the growth of coronary and vascular atheroma.
HISTORY OF THE INVENTION
Oxidation of blood lipoproteins and their deposition from blood into plaque is one of the major contributing factors in the onset of atherogenesis. For example, immunogenic oxidized low density lipoprotein (OxLDL) accumulates in plaque lesions of patients with atherosclerosis to form atheromas. Based on detection of autoantibodies to OxLDL, it also appears to be present in higher serum quantities than normal in patients with coronary artery disease, hypercholesterolemia, diabetes, peripheral vascular disease, hypertension and preeclampsia.
Candidate diagnostic reagents which have been investigated for binding to atherosclerotic plaque components include radiolabeled lipoprotein (LDL), polipoprotein B (apo B), autologous platelets, antifibrin antibodies and components related to smooth muscle cell proliferation. In general, however, such agents suffer from a lack of specificity and are not useful for monitoring the development of oxidation-specific epitopes on lipoproteins which arise during various stages of lipoprotein oxidation and atherosclerotic plaque formation.
SUMMARY OF THE INVENTION
The invention provides a panel of monoclonal antibodies (“E0 antibodies”) that have unique binding specificity for one or more oxidation-specific epitopes on oxidized blood lipoproteins. The binding specificities of different antibodies for oxidation-specific epitopes which arise at various early and late stages of lipoprotein oxidation atheroma formation allows for early detection of plaque as well as monitoring of the oxidation process. To these ends, assay methods are provided by the invention that are based on in vivo and in vitro binding of oxidation-specific epitopes on lipoproteins by E0 antibodies in plasma and in plaque-lesioned tissue.
The E0 antibodies also bind particular oxidation-specific epitopes in a manner which inhibits macrophage-mediated incorporation of oxidized lipoproteins into developing plaque. Therapeutic methods which rely on the E0 antibodies to inhibit the formation of coronary and vascular atheroma are therefore also provided.
For in vitro diagnostic screening use, all or part of the panel of E0 antibodies arc used to measure oxidation-specific epitopes in samples of host plasma or tissue. Expression and proliferation of oxidation-specific epitopes on lipoproteins of blood origin (especially LDL) correlates strongly with the onset and development of plaque lesions in coronary or vascular tissue. In addition, the appearance of epitopes which arise primarily during earlier or later stages of lipoprotein oxidation (which may be discriminated with certain members of the E0 antibody panel) is indicative of the stage of plaque lesion development in the host.
A host who screens positive for the presence of plaque lesions according to the invention is a candidate for further diagnostic evaluation to confirm the location of the lesions and the nature of the disease associated with the lesions (e.g., coronary artery disease). Furthermore, a host who screens positive for a diagnostically significant number of oxidation-specific epitopes induced by exposing a substantially nonoxidized lipoprotein sample from the host to a pro-oxidant is susceptible to plaque formation and a candidate for prophylactic treatment.
For in vivo diagnostic use, all or part of the panel of E0 antibodies are labelled with molecules that are detectable using in vivo imaging techniques and used as agents to image plaque lesions in coronary or vascular vessels.
For monitoring responsiveness to therapy or progression of lipoprotein oxidation, in vitro or in vivo measurements of oxidation-specific epitopes on lipoproteins in plasma or plaque are taken periodically using the same E0 antibodies for each measurement. In general, a decline in oxidation-specific epitope proliferation correlates to a decline in oxidative modification of lipoproteins. The decrease in the availability of oxidized lipoproteins for incorporation into plaque is indicative of a slowing or regression of the oxidation process which leads to atheroma formation. Conversely, increases in these values indicates that atheroma formation is proceeding in the evaluated host.
For use in the in vitro methods of the invention, the invention provides a sensitive sandwich immunoassay. The assay utilizes oxidation-protected LDL or HDL in a plasma or tissue sample obtained from a host in a sandwich with an antibody specific for a component of the lipoproteins and an E0 antibody. Existing oxidation-specific epitopes are measured using this assay technique. Alternatively, a susceptibility to lipoprotein oxidation in a host can be determined by detecting and measuring the type and number of oxidation-specific epitopes which are induced in response to adding a pro-oxidant to the host lipoprotein sample.
REFERENCES:
patent: 0 433 088 A1 (1991-06-01), None
patent: WO 98/12561 (1998-04-01), None
patent: PCT/GB98/00677 (1998-10-01), None
Palinski et al., J. Clinic. Investigation, 98(3), 800-814, Aug. 1, 1996.*
Palinski et al. Low density lipoprotein undergoes oxidative modification in vivo, Proc. Natl. Acad. Sci. USA, vol. 86, pp. 1372-1376, Feb. 1989.
Palinski, et al. Antisera and Monoclonal Antibodies Specific for Epitopes Generated during Oxidative Modification of Low Density Lipoprotein, Arteriosclerosis; vol. 10, (1990) May/Jun. No. 3, pp. 325-335.
Hörkkö Sohvi
Palinski Wulf
Steinberg Daniel
Witztum Joseph L.
Caputa Anthony C.
Foley & Lardner
Tedeschi Bruce
The Regents of the University of California
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