The General Hospital Corporation

Other

Children's Medical Center Corporation

The Charles Stark Draper Laboratory, Inc.

M Amin Arnaout

Jeffrey T Borenstein

Joseph L Charest

Vineet Gupta

Rui Li

Jian-Ping Xiong

John L Niles

Robert T McCluskey

Peter G Linde

Provided herein are integrin antagonists and methods of using the same. For example, one or more of the compounds or polypeptides provided herein can be used in the treatment of disorders such as heart attacks, stroke, and cancer metastasis.

Integrin antagonists

The present application relates to polypeptides which are integrin antagonists. Methods of preparing the integrin antagonists and methods of treating diseases and disorders associated with abnormal levels and/or expression of one or more integrins are also provided.

Polypeptide integrin antagonists

The present application relates to compounds which are integrin antagonists. Methods of preparing the integrin antagonists and methods of treating diseases and disorders associated with abnormal levels and/or expression of one or more integrins are also provided.

This disclosure relates to therapeutic use of integrin-binding antibodies.

Therapeutic use of integrin-binding antibodies

Provided herein are integrin antagonists and methods of using the same. For example, one or more of the compounds or polypeptides provided herein can be used in the treatment of disorders such as heart attacks, stroke, and cancer metastasis. Also provided herein is a crystal comprising &#x3b1;v&#x3b2;3 ectodomain complexed with inhibitor knottin 2.5 F. Further provided herein is a crystal comprising &#x3b1;V&#x3b2;3 ectodomain complexed with inhibitor hFN10. In another aspect, the invention features a method that includes using a three-dimensional model of a complex that includes an integrin ectodomain.

Integrin Antagonists

The application describes an assay for the identification of small molecule modulators of integrin CD11b/CD18 and small molecules capable of modulating activity of this receptor. Such compounds may be used in certain embodiments for treating a disease or condition selected from inflammation, immune-related disorders, cancer, ischemia-reperfusion injury, stroke, neointimal thickening associated with vascular injury, bullous pemphigoid, neonatal obstructive nephropathy, and cardiovascular disease, or in other embodiments for the treatment of a disease or condition selected from immune deficiency, acquired immune deficiency syndrome (AIDS), myeloperoxidase deficiency, Wiskott-Aldrich syndrome, chronic granulomatous disease, hyper-IgM syndromes, leukocyte adhesion deficiency, Chediak-Higashi syndrome, and severe combined immunodeficiency.

Compounds for modulating integrin CD11B/CD18

Compounds for modulating integrin CD11b/CD18

The application describes an assay for the identification of small molecule modulators of integrin CD11b/CD18 and small molecules capable of modulating activity of this receptor. For example, one such compound useful as an agonist of integrin CD11b/CD18 is the compound of Formula (I): Such compounds may be used in certain embodiments for treating a disease or condition selected from inflammation, immune-related disorders, cancer, ischemia-reperfusion injury, stroke, neointimal thickening associated with vascular injury, bullous pemphigoid, neonatal obstructive nephropathy, and cardiovascular disease, or in other embodiments for the treatment of a disease or condition selected from immune deficiency, acquired immune deficiency syndrome (AIDS), myeloperoxidase deficiency, Wiskott-Aldrich syndrome, chronic granulomatous disease, hyper-IgM syndromes, leukocyte adhesion deficiency, Chediak-Higashi syndrome, and severe combined immunodeficiency.

Ligand-mimetic monoclonal antibody mAb 107, produced by a hybridoma cell line deposited in the American Type Culture Collection under Accession Number ATCC PTA-11614, which binds to CD11b MIDAS in an activation-independent manner.

Integrin-binding antibodies

Polypeptides comprising all or part of a variant integrin &#x3b1; subunit A domain and its flanking region are described. In solution or in membrane-associated form, the A domain polypeptides of the invention exists predominantly in a high affinity conformation. In the polypeptides of the invention, referred to as variant integrin polypeptides, a crucial isoleucine or glutamic acid residue is altered. For example, the glutamic acid can be either deleted or replaced with different amino acids residue, e.g., glutamine, aspartic acid, or alanine The variant integrin polypeptides of the invention selectively impair binding of activation-dependent ligands, but not independent ligands. They are useful in screening assays for the identification of molecules that enhance binding of variant polypeptides with impaired binding. In addition, they are useful in distinguishing between activation-dependent ligands and activation-independent ligands. They are also useful for generating antibodies, e.g., monoclonal antibodies, which bind to the impaired form of an integrin. Some such antibodies recognize an epitope that is either not present or not accessible on an integrin that is in the high affinity conformation. The variant integrin polypeptides of the invention can be derived from any integrin &#x3b1; subunit that could be used therapeutically.

Variant integrin polypeptides and uses thereof

Polypeptides comprising all or part of a variant integrin &#x3b1; subunit A domain or a variant integrin &#x3b2; subunit A-like domain are described. In solution or in membrane-associated form, the A domain or the A-like domain of the polypeptides of the invention exists predominantly in a high affinity conformation. In the polypeptides of the invention, referred to as variant integrin polypeptides, a crucial isoleucine residue (described in greater detail below) is absent. The isoleucine can be either deleted or replaced with different amino acids residue, preferably a smaller or less hydrophobic amino acid residue, e.g., alanine or glycine. Because the variant integrin polypeptides of the invention exist in solution or in membrane-associated form predominantly in a high affinity conformation, they are useful in screening assays for the identification of molecules that bind to (and/or mediate the activity of) an integrin. They are also useful for generating antibodies, e.g., monoclonal antibodies, which bind to the high affinity form of an integrin. Some such antibodies recognize an epitope that is either not present or not accessible on an integrin that is in a lower affinity conformation. The variant integrin polypeptides of the invention can be derived from any integrin &#x3b1; subunit or any integrin &#x3b2; subunit and could be used therapeutically. The variant integrin polypeptides preferably include a ligand-binding portion of an A-domain or an A-like domain.

High affinity integrin polypeptides and uses thereof

Flk-1 positive/Sca-1 negative renal stems cells and uses thereof are described. The cells are useful for the regeneration of damaged kidney tissue, the generation of artificial kidneys and the delivery of transgenes.

Renal stem cells and uses thereof

The invention features human CD11 recombinant or synthetic peptide capable of inhibiting a CD11/CD18-mediated immune response, a purified DNA encoding a human CD11b peptide, soluble heterodimeric molecules composed of a CD11 peptide and a CD18 peptide, and a method of controlling any phagocyte-mediated tissue damage such as that associated with reduced perfusion of heart tissue during acute cardiac insufficiency.

Controlling cellular immune/inflammatory responses with .beta.2 integrins

The invention features human CR3.alpha. recombinant or synthetic peptide capable of inhibiting a CR3-mediated immune response, a purified DNA encoding a human CR3.alpha. peptide, and a method of controlling any phagocyte-mediated tissue damage such as that associated with reduced perfusion of heart tissue during acute cardiac insufficiency. As used herein, a human CR3.alpha. recombinant peptide is a chain of amino acids derived from recombinant CR3.alpha.-encoding cDNA, or the corresponding synthetic DNA.

Growing community of inventors

Chestnut Hill, MA, United States of America

M Amin Arnaout