National Institutes of Health, a Component of the US Dept. of Health & Human Services

Leland Stanford Junior University

The United States of America As Represented by the Secretary of

The United States of America As Represented by the Department of Health

Whitehead Institute for Biomedical Research

The Government of the United States of America

University of Washington

Health Research Inc., Roswell Park Division

Health Research Inc. Rosewell Park Division

Warren Jaye Leonard

Rosanne Spolski

Aaron Michael Ring

Christopher K Garcia

Suman Mitra

John J O'Shea

Daniel W McVicar

Herbert C Morse, Iii

Sarah M Russell

Masaru Kawamura

Catherine Rachel Ettinger

Akhilesh Pandey

Peter E Lipsky

Katsutoshi Ozaki

James A Johnston

Harvey F Lodish

Steven D Levin

Heinz Baumann

Andrew G Farr

Nancy F Halden

Julie B Wolf

Warner C Greene

Thomas Alexander Waldmann

Robert Yarchoan

K Christopher Garcia

David A Nelson

Amin Al-Shami

Masayuki Noguchi

O Wesley McBride

Erin Elizabeth West

Laurence Rubin

William Biddison

Gang Wang

Katsutoshi Osaki

Peter Lipski

Herbert C Iii Morse

Novel human interleukin-2 (IL-2) muteins or variants thereof are provided. In particular, provided are IL-2 muteins that have an increased binding capacity for IL-2Rβ receptor and a decreased binding capacity for IL-2Rγreceptor, as compared to wild-type IL-2. Such IL-2 muteins are useful, for example, as IL-2 partial agonist and antagonists in applications where reduction or inhibition of one or more IL-2 and/or IL-15 functions is useful (e.g., in the treatment of graft versus host disease (GVHD) and adult T cell leukemia). Also provided are nucleic acids encoding such IL-2 muteins, methods of making such IL-2 muteins, pharmaceutical compositions that include such IL-2 muteins and methods of treatment using such pharmaceutical compositions.

Superagonists, partial agonists and antagonists of interleukin-2

Novel human interleukin-2 (IL-2) muteins or variants thereof are provided. In particular, provided are IL-2 muteins that have an increased binding capacity for IL-2R&#x3b2; receptor and a decreased binding capacity for IL-2R&#x3b3;receptor, as compared to wild-type IL-2. Such IL-2 muteins are useful, for example, as IL-2 partial agonist and antagonists in applications where reduction or inhibition of one or more IL-2 and/or IL-15 functions is useful (e.g., in the treatment of graft versus host disease (GVHD) and adult T cell leukemia). Also provided are nucleic acids encoding such IL-2 muteins, methods of making such IL-2 muteins, pharmaceutical compositions that include such IL-2 muteins and methods of treatment using such pharmaceutical compositions.

Method of treating graft versus host disease with an interleukin-2 mutein

The invention provides a method of promoting the host defense of a patient to a bacterial infection comprising administering to a patient suffering or at risk of a bacterial infection, a pharmaceutical composition comprising an effective amount of the pleiotropic cytokine, thymic stromal lymphopoietin (TSLP) protein or polypeptide in an amount and at a location sufficient to promote the host defense of the patient to the bacterial infection. In a preferred embodiment, the bacterial infection is the infection of the patient with MRSA. The invention also provides a method of treating blood product, which comprises introducing a TSLP protein or polypeptide into such blood product, wherein the blood product is extracorporeal and comprises at least one neutrophil.

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Novel human interleukin-2 (IL-2) muteins or variants thereof are provided. In particular, provided are IL-2 muteins that have an increased binding capacity for IL-2RP receptor and a decreased binding capacity for IL-2R&#x3a5;receptor, as compared to wild-type IL-2. Such IL-2 muteins are useful, for example, as IL-2 partial agonist and antagonists in applications where reduction or inhibition of one or more IL-2 and/or IL-15 functions is useful (e.g., in the treatment of graft versus host disease (GVHD) and adult T cell leukemia). Also provided are nucleic acids encoding such IL-2 muteins, methods of making such IL-2 muteins, pharmaceutical compositions that include such IL-2 muteins and methods of treatment using such pharmaceutical compositions.

The invention provides a method for promoting differentiation of a mature na&#xef;ve B cell or a B cell progenitor into a memory B cell or a plasma cell. The method comprises (a) contacting a population of cells comprising a mature na&#xef;ve B cell or a B cell progenitor with an agent that activates at least one of JAK1, JAK3, STAT3, STAT5A or STAT5B; wherein the population of cells optionally is contacted with an antigen, and (b) isolating the memory B cell or plasma cell.

Method of inducing memory B cell development and terminal differentiation

A method is disclosed herein for inducing differentiation of a B cell progenitor into a memory B cells and/or a plasma cell. The method includes contacting a population of cells including a mature B cell or a B cell progenitor with an effective amount of IL-21, and isolating memory B cells or plasma cells. In one embodiment, the B cell progenitor is an immature B cell. A method is also disclosed for enhancing an immune response. The method includes contacting a population of cells including a B cell progenitor with an effective amount of IL-21, and isolating memory B cells or plasma cells. The memory B cells arid/or the plasma cell are then introduced into the subject to enhance the immune response. A method is also disclosed for treating a subject with a condition comprising a specific deficiency of at least one of memory B cells and plasma cells. A method is disclosed for identifying an agent with a physiological effect on one or more of a memory B cell and a plasma cell differentiation. A method is also disclosed for identifying agents that inhibit an activity of IL-21.

An isolated polynucleotide encodes JAK-3 protein. JAK-3 protein is a protein tyrosine kinase having a molecular weight of approximately 125 kDa which has tandem non-identical catalytic domains, lacks SH2 or SH3 domains, and is expressed in NK cells and stimulated or transformed T cells, but not in resting T cells. The protein itself and antibodies to this protein are also presented. Further, methods of identifying therapeutic agents for modulating the immune system make use of the foregoing.

Janus family kinases and identification of immune modulators

Methods are disclosed herein for specifically inducing proliferation of CD4T cells. The methods are of use in treating immunodeficiencies, such as an immunodeficiency produced by infection with an immunodeficiency virus, such as infection with a human immunodeficiency virus (HIV). The methods include contacting isolated mammalian CD4+ T cells with an effective amount of a thymic stromal derived lymphopoietin (TSLP) polypeptide or a therapeutically effective amount of nucleic acid encoding the TSLP polypeptide, thereby inducing proliferation of the T cells. Methods are also disclosed for treating an IgE mediated disorder, such as asthma. The methods include administering to a subject a therapeutically effective amount of a TSLP antagonist. Transgenic mice are also disclosed herein. The somatic and germ cells of these mice include a disrupted thymic stromal lymphopoietin receptor (TSLP) gene, the disruption being sufficient to inhibit the interaction of TSLP with its receptor, and a disrupted &#x3b3;gene, the disruption being sufficient to reduce signaling through the &#x3b3;. The mice exhibit diminished thymic cellularity. Methods of using these mice for drug screening are also disclosed.

Methods for use of TSLP and agonists and antagonists thereof

The present invention provides Thymic Stromal Lymphopoietin Receptor (TSLPR) polypeptides and nucleic acid molecules encoding the same. The invention also provides selective binding agents, vectors, host cells, and methods for producing TSLPR polypeptides. The invention further provides pharmaceutical compositions and methods for the diagnosis, treatment, amelioration, and/or prevention of diseases, disorders, and conditions associated with TSLPR polypeptides.

Thymic stromal lymphopoietin receptor molecules and uses thereof

A method is disclosed herein for inducing differentiation of a B cell progenitor into a memory B cells and/or a plasma cell. The method includes contacting a population of cells including a mature B cell or a B cell progenitor with an effective amount of IL-21, and isolating memory B cells or plasma cells. In one embodiment, the B cell progenitor is an immature B cell. A method is also disclosed for enhancing an immune response. The method includes contacting a population of cells including a B cell progenitor with an effective amount of IL-21, and isolating memory B cells or plasma cells. The memory B cells and/or the plasma cell are then introduced into the subject to enhance the immune response. A method is also disclosed for treating a subject with a condition comprising a specific deficiency of at least one of memory B cells and plasma cells. A method is disclosed for identifying an agent with a physiological effect on one or more of a memory B cell and a plasma cell differentiation. A method is also disclosed for identifying agents that inhibit an activity of IL-21. Methods are also disclosed for inducing apoptosis of a B cell and for decreasing the number of B cells. A method is also described for producing a B cell hybridoma.

A transgenic mouse is disclosed herein whose somatic and germ cells comprise a disrupted IL-21 receptor gene, the disruption being sufficient to inhibit the binding of IL-21 to an IL-21 receptor, and a disrupted IL-4 gene, the disruption being sufficient to inhibit the production of IL-4 or the binding of IL-4 to the IL-4 receptor. A mouse homozygous for the disrupted IL-21 receptor gene and homozygous for the disrupted IL-4 gene has diminished B cell function. A method is disclosed for altering a B cell activity. The method includes administering a therapeutically effective amount of an agent that interferes with the interaction of IL-21 with an IL-21 receptor, thereby altering the B cell activity. A method is also disclosed for of treating a subject with Job's disorder or atopic disease. A method is also disclosed for treating or preventing an allergic reaction in a subject. A method is also disclosed for treating a subject with an autoimmune or antibody mediated disorder.

IL-21 as a regulator of immunoglobin production

Growing community of inventors

Bethesda, MD, United States of America

Warren Jaye Leonard