Oklahoma Medical Research Foundation

Abbott Cardiovascular Systems, Inc.

Other

Genentech, Inc.

Baptist Medical Center of Oklahoma, Inc.

Integris Baptist Medical Center, Inc.

Eugen Koren

Mirna Koscec

Morris Reichlin

David K Cooper

John Hok Nin Lowe

David K C Cooper

Wei Zhang

A method of determining the thrombogenicity of an implantable medical device is disclosed. The implanted device is exposed in vitro to platelet rich plasma, the activity of an indicator is assayed, and the thrombogenicity is determined.

Method for thrombogenicity testing of implanted medical device

Compositions and methods using antibodies which are immunoreactive with specific apolipoproteins to determine the concentrations of lipoproteins such as HDL and LDL, and/or apolipoproteins in human blood, serum or plasma sample, are described. Monoclonal antibodies (MAbs) are described that specifically bind to epitopes present in apolipoproteins and lipoproteins, enabling rapid and reliable determinations of levels of specific blood lipoprotein and/or apolipoprotein levels, including Apo B-100, Apo A-I, Apo A-II, Apo C-III, and Apo E, and thereby determination of relative ratios of HDL and LDL and LpaI and LpaII. In a preferred embodiment, the compositions are strips of a solid phase material coated with one or more of the antibodies and are referred to herein as 'dipsticks'. The dipsticks specifically bind a lipoprotein or apolipoprotein when dipped into a protein sample. The amount of lipid associated with a bound lipoprotein or the amount of apolipoprotein bound on the dipstick is quantitated using an appropriate method, for example, by staining with a lipid stain or reaction with a second labelled antibody. The intensity of the stain on the dipstick is proportional to the concentration of the lipoprotein lipid or apolipoprotein circulating in the blood and can be quantitated by comparison with standards containing known amounts of lipid.

Antibodies to lipoproteins and apolipoproteins and methods of use thereof

The invention provides for methods of modifying immunodominant epitopes on polypeptides, preferably polypeptides intended for therapeutic use. Knowledge of immunodominant epitopes prior to clinical use of polypeptides would be useful to design and engineer less immunogenic molecules. The invention provides for methods of identifying immunodominant epitopes and modifying an immunodominant epitope to reduce the immune response to the polypeptide while still retaining a substantial therapeutic activity of the polypeptide. The modified polypeptides are useful therapeutically.

Identification and modification of immunodominant epitopes in polypeptides

Treatments have been developed for lupus patients using either anti-ID antibodies to dsDNA to block anti-dsDNA antibodies and/or kill the B cells producing the anti-dsDNA antibodies or ribosomal protein S1 peptides immunoreactive with anti-dsDNA antibodies. Examples demonstrate that (1) anti-dsDNA antibodies are cross-reactive with ribosomal protein S1, (2) anti-dsDNA antibodies suppress protein synthesis, presumably through inhibition of mRNA translation initiation, and (3) a normal human sera contains an anti-idiotypic antibody (anti-Id) to anti-dsDNA antibodies isolated from SLE patients which blocked the interactions between the anti-Id antibody fragment (Fab ) and various anti-dsDNA preparations.

Method for treatment of SLE

Methods to manipulate animals such as pigs, and the animals and tissues thereby derived, to reduce their immunogenicity following implantation into humans, are described. These methods are based on the discovery that certain carbohydrate structures on pig tissues, which require expression of the gene encoding the &agr; 1&rarr;3 galactosyl transferase enzyme, are targets for natural preformed antibodies of humans and elicit further antibody production in humans, while other carbohydrate structures do not or do so in a reduced amount. In the preferred embodiment, animals are produced by homologous recombination of the gene encoding &agr; 1&rarr;3 galactosyl transferase in embryonic stem cells or by microinjection into embryos of sequences eliminating or decreasing expression of &agr; 1&rarr;3 galactosyl transferase. In alternative embodiments, animals are produced having reduced amounts of &agr; 1&rarr;3 galactosyl epitopes or epitopes which are masked by sialylation or fucosylation.

Genetically engineered mammals for use as organ donors

Assays that are prognostic for patients that will develop nephritis have been developed where patient serum is screened for the presence of anti-dsDNA antibodies that are cross reactive with A and D SnRNP proteins. The assays are based on the use of either peptides containing epitopes bound by the anti-dsDNA antibodies, or the antigens for the antibodies, A and D SnRNP proteins. Therapeutic compositions have also been developed using either antibodies that block the pathogenicity of the anti-dsDNA antibodies, such as the naturally occurring anti-La/SSB, anti-Ro/SSA and anti-U,RNP antibodies that are cross reactive with the anti-dsDNA or using the peptides or A and D proteins to induce tolerance.

Assay for pathogenicity of anti-DNA antibodies

Antibodies directed against idiotypes on naturally occurring human anti-animal antibodies are disclosed for use in inhibiting xenograft rejection in human patients. An effective quantity of these anti-idiotypic antibodies is injected into the actual or potential xenograft recipient in order to bind to the idiotypes expressed on anti-animal antibodies as well as subpopulations of B lymphocytes, to inhibit hyperacute rejection of transplanted animal tissues or organs by the human patient. Alternatively, anti-idiotypic antibodies are used in the form of immunoaffinity columns to deplete anti-animal antibodies from the recipient's serum. Methods of making mouse monoclonal, mouse recombinant, and human recombinant anti-idiotypic antibodies are described, as well as immunoaffinity columns containing immobilized anti-idiotypic antibodies. A method and means for assessing the expected character and severity of a patient's rejection response to transplanted animal tissues is described, as well as methods of identification, isolation and suppression of lymphocytes bearing anti-animal idiotypes.

Anti-idiotypic antibody composition for inhibiting acute

Assays that are prognostic for patients that will develop nephritis have been developed where patient serum is screened for the presence of anti-dsDNA antibodies that are cross reactive with A and D SnRNP proteins. The assays are based on the use of either peptides containing epitopes bound by the anti-dsDNA antibodies, or the antigens for the antibodies, A and D SnRNP proteins. Therapeutic compositions have also been developed using either antibodies that block the pathogenicity of the anti-dsDNA antibodies, such as the naturally occurring anti-La/SSB and anti-U.sub.1 RNP antibodies that are cross reactive with the anti-dsDNA or using the peptides or A and D proteins to induce tolerance.

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San Francisco, CA, United States of America

Eugen Koren