The General Hospital Corporation

Bristol-myers Squibb Compnay

Harvard College

Massachusetts General Hospital Corporation

Gary R Matsueda

Edgar Haber

Guy L Reed

Mei-Yin Hsu

James K Tamura

Kwan Hui

Jurgen Bajorath

Wen-Pin Yang

Akbar Nayeem

Linda Harris

Jiri Novotny

Michael N Margolies

Shyh-Yu Shaw

Paul H Ehrlich

The present invention relates to the isolation and identification of novel baboon nucleic acid molecules and proteins and polypeptides encoded by such nucleic acid molecules, or degenerate variants thereof, which proteins and polypeptides comprise novel baboon thrombin-activatable fibrinolysis inhibitors or 'TAFI' enzyme molecules. Because the novel baboon TAFI proteins and polypeptides of the invention inhibit the breakdown of blood clots, they may be therapeutically useful for the treatment of blood disorders wherein clotting needs to be regulated or promoted, such as hemophilia or von Willebrand's disease or in other situations, such as trauma, wherein blood clotting or coagulation needs to be regulated or promoted. The sequences of the invention are also useful in screening methods for the identification of compounds that modulate the expression of the baboon TAFI nucleic acids and/or the activity of the baboon TAFI proteins and polypeptides of the invention. Such agonist or antagonist compounds may be useful in the treatment of various blood clotting disorders and conditions requiring hemostatic control such as hemophilia or various thrombotic diseases such as deep venous thrombosis, coronary artery disease, stroke associated with atrial fibrillation and recurrent thrombosis following stroke or myocardial infarction.

Baboon TAFI polypeptides

Nucleic acid molecules and polypeptides encoding baboon TAFI

The present invention relates to a treatment for myocardial infarction and blood clots within a patient, and more specifically to a therapy which enhances clot lysis comprising administering to a patient an antibody directed to &agr;2-antiplasmin crosslinked to fibrin (&agr;2AP-FX) which does not inhibit plasma &agr;2-antiplasmin (&agr;2AP). The invention also relates to a treatment for enhancing clot lysis comprising administering an antibody directed toward &agr;2-antiplasmin crosslinked to fibrin which does not inhibit plasma &agr;2AP together with a thrombolytic agent.

Antibodies that bind to &agr;2-antiplasmin crosslinked to fibrin which do not inhibit plasma &agr;2-antiplasmin

The present invention relates to a novel alpha-2-antiplasmin-binding molecules and treatment for pulmonary embolism, myocardial infarction, thrombosis or stroke in a patient which comprises administering an alpha-2-antiplasmin-binding molecule capable of preventing inhibition of plasmin by endogenous alpha-2-antiplasmin. The invention also relates to a treatment for pulmonary embolism, myocardial infarction, thrombosis or stroke in a patient comprising coadministrating an alpha-2-antiplasmin-binding molecule of the invention together with a thrombolytic agent.

Composition and method for enhancing fibrinolysis

The present invention relates to a treatment for myocardial infarction and blood clots within a patient, and more specifically to a therapy which enhances clot lysis comprising administering to a patient an antibody directed to .alpha.2-antiplasmin crosslinked to fibrin (.alpha.2AP-FX) which does not inhibit plasma .alpha.2-antiplasmin (.alpha.2AP). The invention also relates to a treatment for enhancing clot lysis comprising administering an antibody directed toward .alpha.2-antiplasmin crosslinked to fibrin which does not inhibit plasma .alpha.2AP together with a thrombolytic agent.

Antibodies that bind to .alpha.2-antiplasmin crosslinked to fibrin which

The present invention provides a thrombin-activated platelet protein (TAPP). The protein is selectively expressed on the surface of thrombin-activated platelets. Antibodies which selectively bind to the thrombin-activated platelet protein are also provided. These compositions find use in the detection and treatment of blood clots.

Activation-dependent protein expressed on the surface of activated

Methods of inhibiting the activation of Factor XIII

The present invention relates to a treatment for myocardial infarction and blood clots within a patient, and more specifically to a therapy which enhances clot lysis comprising administering to a patient an antibody directed to .alpha.2-antiplasmin crosslinked to fibrin (.alpha.2AP-Fx) which does not inhibit plasma .alpha.2-antiplasmin (.alpha.2AP). The invention also relates to a treatment for enhancing clot lysis comprising administering an antibody directed toward .alpha.2-antiplasmin crosslinked to fibrin which does not inhibit plasma .alpha.2AP together with a thrombolytic agent.

A new chimeric plasminogen activator with high fibrin affinity was designed to bind to a fibrin clot and initiate clot destruction in the presence of thrombin, but not plasmin. The chimeric molecule has an antibody variable region having a fibrin-specific antigen binding site and a single chain urokinase region having a thrombin activation site but not a plasmin activation site. The preferred embodiment, 59D8-ScuPA-T, has an N-terminal fragment of an anti-fibrin antibody (59DB) and a C-terminal thrombin-activatable low molecular weight single-chain urokinase plasminogen activator (scuPA-T). The scuPA-T portion was obtained by deletion of two amino acids (Phe157 and Lys 158) that make up the plasmin activation site from low molecular weight single chain urokinase-type plasminogen activator (scuPA).

Thrombin-activatable plasminogen activator

Thrombin-activated platelet protein-2 (TAPP-2)

The present invention relates to a novel treatment for blood clots within a patient or myocardial infarction which comprises administering a hapten-binding molecule capable of preventing inhibition of plasmin by endogenous alpha-2-antiplasmin. The invention also relates to a treatment for blood clots within a patient or myocardial infarction comprising coadministrating the hapten-binding molecule of the invention together with a thrombolytic agent capable of either dissolving fibrin-platelet clots or inhibiting their formation. The therapy of the invention is capable of increasing clot lysis while minimizing fibrinogen breakdown and preventing the reocclusion of the affected coronary artery. The therapy of the present invention is capable of achieving this goal even in the absence of heparin and when the concentration of thrombolytic agent is lower than that required by other potential therapies.

Composition and method for acceleration of clot lysis

Peptides comprising fibrin-specific epitopic sequences are used to prepare hybridoma cell lines producing antifibrin-specific monoclonal antibodies substantially devoid of fibrinogen-cross-reactivity obtained by somatic cell fusion. The antibodies are useful for the in vivo and in vitro detection of thrombi and fibrin deposits.

Synthetic peptides capable of eliciting fibrin-specific monoclonal

Disclosed is a method for the in vivo lysis of a thrombus in a host by administration of a conjugate consisting of a monoclonal antibody specific for fibrin coupled to a plasminogen activator such as tissue plasminogen activator, urokinase or streptokinase.

Method and use for site-specific activation of substances

A thrombolytic product comprising a fibrin-specific antibody substantially devoid of fibrinogen cross-reactivity coupled to a thrombolytic agent.

Growing community of inventors

Princeton, NJ, United States of America

Gary R Matsueda