Alexion Pharmaceuticals, Inc.

Oklahoma Medical Research Foundation

Yale University

Selexys Pharmaceuticals Corporation

Bioprocessors Corp.

Scott A Rollins

Stephen P Squinto

Russell P Rother

Louis A Matis

Jeremy P Springhorn

Richard A Flavell

Peter J Sims

Leonard Bell

Mark James Evans

Richard Alvarez

Joseph A Madri

William L Fodor

Eileen A Elliot

Rodger P McEver

Alfred L Bothwell

Allyn E Hubbard

Ziad Kawar

Samesh Kale

Yi Wang

Steven H Nye

James M Mason

Eileen Elliott Mueller

James A Wilkins

Thomas C Thomas

Prasad R Akkapeddi

Alfred L M Bothwell

Brian R Smith

Ziad S Kawar

Rodger P Mcever

Eileen Mueller

Antibodies are disclosed which bind specifically to P-selectin and which block the binding of PSGL-1 to P-selectin. These anti-P-selectin antibodies may also cause dissociation of preformed P-selectin/PSGL-1 complexes. The disclosure identifies a heretofore unrecognized, near N-terminal, antibody binding domain (a conformational epitope) of P-selectin to which the function-blocking antibodies (which may be chimeric, human or humanized antibodies for example) bind. Antibodies are disclosed which bind to the conformational epitope of P-selectin and which have a dual function in blocking binding of PSGL-1 to P-selectin, and in causing dissociation of preformed P-selectin/PSGL-1 complexes. Such single and dual function anti-P-selectin antibodies and binding fragments thereof may be used in the treatment of a variety of inflammatory and thrombotic disorders and conditions. Screening methods for identifying such antibodies are also disclosed.

Anti-P-selectin antibodies

Methods of treating inflammatory or thrombotic conditions with anti-P-selectin antibodies

The present invention is directed to antibodies and binding fragments thereof, which bind with high affinity and specificity to human P-selectin glycoprotein ligand 1 (PSGL-1) and which block both selectin and chemokine binding to PSGL-1 expressed on leukocytes, lymphocytes and endothelial cells and thus which inhibit migration and/or rolling of these cells and to methods for screening for such antibodies and binding fragments thereof and to methods of therapeutic use thereof.

Methods of inhibiting the PSGL-1-mediated adhesion and chemokine-mediated migration with PSGL-1-specific antibodies

Genetically engineered cells are provided which can serve as universal donor cells in such applications as reconstruction of vascular linings or the administration of therapeutic agents. The cells include a coding region which provides protection against complement-based lysis, i.e., hyperacute rejection. In addition, the cell's natural genome is changed so that functional proteins encoded by either the class II or both the class I and the class II major histocompatibility complex genes do not appear on the cell's surface. In this way, attack by T-cells is avoided. Optionally, the cells can include a self-destruction mechanism so that they can be removed from the host when no longer needed.

Universal donor cells

In a liquid handling system including a liquid handling substrate having a plurality of channels for conducting a liquid sample in said substrate, where the channels terminate in a plurality of exit ports in an outer surface of the substrate for transfer of a quantity of the liquid sample. The handling system also includes a liquid storage and dispensing substrate having a plurality of separable cartridges corresponding to the channels, with each cartridge terminating at a microelectro mechanical system (MEMS) comprising a laminate of glass, silicon and a piezoelectric substance. The handling system further includes a liquid detecting system comprising a light emitting diode and a photo-detector, where each channel includes a reservoir in communication with a corresponding cartridge creating an interface therebetween. The handling system enables a method for storing and dispensing liquids including drawing a liquid sample into the channels either by capillary action, vacuum, electrostatic flow, a minipump or any combination thereof, storing the liquid sample into the cartridge, and dispensing the liquid sample.

Methods and devices for storing and dispensing liquids

The use of anti-C5 antibodies, e.g., monoclonal antibodies, to treat glomerulonephritis (GN) is disclosed. The administration of such antibodies at low dosage levels has been found to significantly reduce glomerular inflammation/enlargement and other pathologic conditions associated with GN. Also disclosed are anti-C5 antibodies and anti-C5 antibody-encoding nucleic acid molecules. These antibodies are useful in the treatment of GN and other inflammatory conditions involving pathologic activation of the complement system.

C5-specific antibodies for the treatment of inflammatory diseases

An apparatus for performing a assays includes an axially rotatable substrate including a plurality of layers of a semiconductor material and numerous radially-arrayed reaction sites. The apparatus further includes a rotary stepper motor which rotates the substrate at an adjustable and substantially continuous speed and controls the rotation of the substrate by adjusting the speed and a direction of rotation. In addition, the apparatus includes a dual function head which has a fluid dispenser that has a fluid dispenser outlet and delivers a fluid to a reaction site and also has a readout device that has a sensor which receives an identifying signal from the reaction site on the substrate or scans the substrate to read identifying marks at the reaction site. Moreover, the apparatus may be aligned by a computer having a memory for storing a start location for the dispenser outlet on the substrate and additional electronics. The computer provides movement signals to the rotary stepper motor and a linear stepper motor on which the dispenser outlet is mounted, whereby the motors align the dual function head over the substrate, such that the dispenser outlet is aligned over the reaction site.

Apparatus for performing assays at reaction sites

The use of anti-C5 antibodies, e.g., monoclonal antibodies, to treat glomerulonephritis (GN) is disclosed. The administration of such antibodies at low dosage levels has been found to significantly reduce glomerular inflammation/enlargement and other pathologic conditions associated with GN.

Use of antibodies specific to human complement component C5 for the

A porcine E-selectin protein, its amino acid sequence, the sequence of a cDNA encoding the protein, antibodies reactive with the protein, and methods for the use of these molecules are disclosed. The molecules are used to diagnose the rejection of xenotransplanted pig organs, as well as to prevent and treat such transplant rejection.

Porcine E-selectin

Methods and compositions are provided for facilitating gene therapy procedures involving the transduction of target cells with retroviral vector particles in the presence of complement containing body fluids. The reduction of levels of galactose alpha (1,3) galactosyl epitopes on the retroviral vector particles and/or the blockade of antibody binding to such epitopes have been found to render the particles less sensitive to inactivation by complement mediated mechanisms, and to thus allow transduction in the presence of complement containing body fluids. Means are provided for obtaining such reductions.

Methods and compositions for protecting retroviral vector particles and

The use of anti-C5 antibodies to reduce the dysfunction of the immune and hemostatic systems associated with extracorporeal circulation procedures, such as, cardiopulmonary bypass procedures, is disclosed. The antibodies have been found to significantly reduce complement activation, platelet activation, leukocyte activation, and platelet-leukocyte adhesion associated with such procedures.

Use of C5-specific antibodies for reducing immune and hemostatic

Nucleic acid sequences encoding chimeric proteins that comprise a functional portion of a parent terminal complement inhibitor, such as CD59, and a heterologous transmembrane domain are provided. The parent terminal complement inhibitor is modified to inactivate its GPI signal sequence. The heterologous transmembrane domain serves to anchor the chimeric protein to the cell membrane without substantially interfering with the complement inhibitor activity of the terminal complement inhibitor. The nucleic acid sequences and encoded chimeric proteins can be used to protect cells from complement attack.

Terminal complement inhibitor fusion proteins

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Monroe, CT, United States of America

Scott A Rollins