Alexion Pharmaceuticals, Inc.

Yale University

Oklahoma Medical Research Foundation

The United States of America, As Represented by the Secretary, Department of Health and Human Services

Bioprocessors Corp.

Regeneron Pharmacueticals, Inc.

Stephen P Squinto

Scott A Rollins

Russell P Rother

Leonard Bell

Jeremy P Springhorn

Richard A Flavell

Peter J Sims

Joseph A Madri

William L Fodor

Eileen A Elliot

Louis A Matis

Alfred L Bothwell

Camille Bedrosian

Allyn E Hubbard

Steven H Nye

James M Mason

Samesh Kale

James A Wilkins

Eileen Elliott Mueller

George D Yancopoulos

Samuel H Davis

Michael J Lenardo

Mark James Evans

Henry McFarland

John P Mueller

Thomas C Thomas

Prasad R Akkapeddi

Alfred L M Bothwell

Clara M Pelfrey

Brian R Smith

Yi Wang

Eileen Mueller

The present disclosure relates to, inter alia, compositions containing an inhibitor of human complement and use of the compositions in methods for treating or preventing complement-associated disorders. In some embodiments, the inhibitor is chronically administered to patients. In some embodiments, the inhibitor is administered to a patient in an amount and with a frequency to maintain systemic complement inhibition and prevent breakthrough. In some embodiments, the compositions contain an antibody, or antigen-binding fragment thereof, that binds to a human complement component C5 protein or a fragment of the protein such as C5a or C5b.

Methods for treating complement-associated disorders

Methods and compositions for treating complement-associated disorders

Compositions and methods are provided for the clinical assessment, diagnosis, and treatment of multiple sclerosis. The compositions of the invention are molecules related to the 21.5 kDa fetal isoform of human myelin basic protein, and include nucleic acids and polypeptides. The nucleic acid molecules of the invention are useful in the efficient production of modified and unmodified 21.5 kDa myelin basic protein polypeptides, such polypeptides being useful for assaying T cells for responsiveness to myelin basic protein epitopes. The polypeptides of the invention are also useful as therapeutic agents that act by inducing T cell responses, including apoptosis, as a means of treating multiple sclerosis.

Modified myelin basic protein molecules

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

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

Modified retroviral vector particles and modified retroviral producer cells producing such particles 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 modifications involve genetic alterations to effect the expression by these cells and particles of complement inhibitor activity. The genetic alterations involve the introduction of nucleic acid expression constructs directing the expression of retroviral SU(gp70)/complement inhibitor chimeric proteins into cells from which the producer cells are derived.

Retroviral vector particles expressing complement inhibitor activity

Chimeric complement inhibitor proteins are provided which include a first functional domain (first amino acid sequence) having C3 inhibitory activity and a second functional domain (second amino acid sequence) having C5b-9 inhibitory activity. The first functional domain is amino terminal to the second functional domain. In this way, the chimeric protein exhibits both C3 and C5b-9 inhibitory activity. The other orientation, i.e., the orientation in which the second amino acid sequence is amino terminal to the first amino acid sequence, only produces C3 inhibitory activity. Nucleic acid molecules encoding such proteins are also provided.

Chimeric complement inhibitor proteins

Nucleic acid encoding chimeric complement inhibitor proteins

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Bethany, CT, United States of America

Stephen P Squinto