The University of Oklahoma

Oklahoma Medical Research Foundation

Selexys Pharmaceuticals Corporation

Centocor, Inc.

Other

Southpac Trust International Inc.

Xia, Lijun

Mcever, Rodger P.

Rodger P McEver

Richard D Cummings

Kevin L Moore

Lijun Xia

Richard Alvarez

Ziad Kawar

Russell P Rother

George A Heavner

Scott A Rollins

Jian-Guo Geng

Peter E Daddona

Douglas James Riexinger

Marian Kruszynski

Leon A Epps

Miljenko Mervic

Harvey J Berger

Junliang Pan

Ziad S Kawar

A population of cells possesses enhanced selectin binding based upon a fucosylated selectin ligand present on a surface thereof. Methods of producing the population of cells, along with therapeutic methods of using the cells, are also disclosed.

Cells treated by in vitro fucosylation and methods of production and use thereof

The invention features antibodies, e.g., chimeric and humanized antibodies, that recognize (i.e., bind) P-selectin. The P-selectin antibodies prevent P-selectin from binding to its cognate receptor. The P-selectin antibodies can be used to treat inflammatory and thrombotic conditions, e.g., sickle cell disease, pain crisis associated with sickle cell disease, deep vein thrombosis, asthma, rheumatoid arthritis, psoriasis, and ischemia reperfusion injury in a patient in need thereof.

Methods of treating sickle cell disease with anti-P-selectin antibodies

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

A method of in vitro fucosylation of selectin ligands on cord blood-derived hematopoietic stem cells for bone marrow transplantation is disclosed. In this method, an effective amount of an &#x3b1;1,3-fucosyltransferase, e.g., &#x3b1;1,3-fucosyltransferase VI, is used in vitro to treat cord blood-derived hematopoietic stem cells to convert non-functional PSGL-1 or other ligands on the cell surface into functional forms that bind selectins, especially P-selectin or E-selectin. The treated cells have enhanced effectiveness in reconstituting bone marrow in patients in need of such therapy.

Stem cells treated by in vitro fucosylation and methods of use

Anti-P-selectin antibodies and methods of using the same to treat inflammatory diseases

Hematopoietic stem cells treated by in vitro fucosylation and methods of use

Compounds, compositions and methods for treating conditions characterized by leukocyte rolling are described. The compounds contain glycosulfopeptide structures comprising sulfated tyrosines and sialyated, fucosylated N-acetyllactosamino glycans. The glycosulfopeptides may be conjugated or complexed to other compounds for enhancing serum half-life or for controlled release, for example. Examples of conditions treated include inflammation, ischemia-reperfusion injury, rheumatoid arthritis, atherosclerosis, leukocyte-mediated lung injury, restenosis, and thrombosis.

Glycosulfopeptide inhibitors of leukocyte rolling and methods of use thereof

A new class of synthetic glycosulfopeptides (GSPs) which have one or more sulfated tyrosine residues and a glycan linked to the peptide, the glycan preferably including a sialyl Lewisgroup or a sialyl Lewisgroup. In a preferred version the GSPs have an O-glycan comprising a &#x3b2;1,6 linkage to a GalNAc. The present invention further contemplates in vitro methods of the synthesis of these GSPs without the use of the cells and methods of their use in vivo as powerful anti-inflammatory antithrombotic, or anti-metastatic compounds. The invention also contemplates a method of synthesizing oligosaccharides by cleaving the glycan from the GSP.

Synthetic glycosulfopeptides and methods of synthesis thereof

P-selectin has been demonstrated to bind primarily to a single major glycoprotein ligand on neutrophils and HL-60 cells, when assessed by blotting assays and by affinity chromatography of &lsqb; H&rsqb;glucosamine-labeled HL-60 cell extracts on immobilized P-selectin. This molecule was characterized and distinguished from other well-characterized neutrophil membrane proteins with similar apparent molecular mass. The purified ligand, or fragments thereof (including both the carbohydrate and protein components), or antibodies to the ligand, or fragments thereof, can be used as inhibitors of binding of P-selectin to cells, and to treat various conditions involving leukocyte binding via P-selectin glycoprotein ligand.

Methods of treatment using antibodies to P-selectin glycoprotein ligand

A new class of synthetic glycosulfopeptides (GSPs) which have one or more sulfated tyrosine residues and a glycan linked to the peptide, the glycan preferably including a sialyl Lewis group or a sialyl Lewis group. In a preferred version the GSPs have an O-glycan comprising a &bgr;1,6 linkage to a GalNAc. The present invention further contemplates in vitro methods of the synthesis of these GSPs without the use of the cells and methods of their use in vivo as powerful anti-inflammatory antithrombotic, or anti-metastatic compounds. The invention also contemplates a method of synthesizing oligosaccharides by cleaving the glycan from the GSP.

Growing community of inventors

Oklahoma City, OK, United States of America

Rodger P McEver