Leland Stanford Junior University

Lumen Therapeutics, LLC

Argos Therapeutics, Inc.

C Garrison Fathman

Edgar George Engleman

Jonathan B Rothbard

Paul Leo McGrane

Erik Kreider

Debra Bloom

Luis R Soares

Charles Nicolette

Remi Creusot

Gregory Ford

Sarah Slaymaker

Provided herein are methods and compositions for treating inflammatory disease by the administration, to a patient in need thereof, of an inhibitor of IL-2R desensitization in combination with a low dose of IL-2. A low dose of interleukin-2 (IL-2) is sufficient to stimulate regulatory T lymphocytes (Tregs) without substantially inducing effector T lymphocytes (Teffs). In some embodiments, the inhibitor of IL-2R desensitization is a small molecule or drug. Is some embodiments the inhibitor is a NEDD8 activating enzyme (NAE) inhibitor. In some embodiments a combination therapy provides for a synergistic effect, where the combination of the inhibitor of IL-2R desensitization and low dose IL-2 provides an effect that is greater than the sum of either the inhibitor or low dose IL-2 administered as a single agent.

Combination of low dose IL-2 and an inhibitor of Treg IL-2R desensitization to treat autoimmune and allergic inflammatory diseases

This invention relates to compositions and methods for treatment of vascular conditions. The invention provides arginine polymers and arginine homopolymers for the treatment and/or prevention of glaucoma, pulmonary hypertension, asthma, chronic obstructive pulmonary disease, erectile dysfunction, Raynaud's syndrome, heparin overdose, vulvodynia, and wound healing. The invention also provides arginine polymers and arginine homopolymers for use in organ perfusate and preservation solutions.

Compositions and methods for treating diseases

A method is provided for treating or preventing an undesired immune response in a patient, comprising: administering to said patient, cells that transiently express, and/or that are transfected with mRNA encoding, one or more polypeptides selected from the group consisting of an IL-4 receptor agonist, an IFN-&#x3b3; receptor antagonist, an IFN-&#x3b1; receptor antagonist, an IL-12 receptor antagonist, an IL-23 receptor antagonist, and a TNF antagonist. Preferably, the cells selectively accumulate in one or more secondary lymphoid tissues at or proximate to the site of the undesired immune response. Related compositions are provided. The methods and compositions are useful for the treatment or prevention of undesired immune responses including, but not limited to, transplant rejection, autoimmune disease, allergy and immune responses directed against therapeutic compositions.

Transient expression of immunomodulatory polypeptides for the prevention and treatment of autoimmune disease, allergy and transplant rejection

An active ubiquitin E3 ligase, GRAIL, is crucial in the induction of anergy in cells of the immune system, and in the regulation of cellular proliferation. GRAIL is shown to associate with, and be regulated by Otubain isoforms, including OTUBAIN-1 (DOG, the Destabilizer of GRAIL) and an alternative reading frame splice variant of OTUBAIN-1 (SOG, the Stabilizer of GRAIL). These proteins play opposing roles in the regulation of GRAIL auto-ubiquitination and consequently on its ability to induce anergy and regulate cellular proliferation. DOG serves as an adaptor protein, recruiting the DUB USP8. One major substrate for USP8 is the Ras exchange factor Ras-GRF1, and this protein can be found in a complex with USP8 and GRAIL, which complex is ubiquitinated by GRAIL.

Polypeptide complex that regulates cell cycle and anergy

Autoimmune disease is treated by the delivery of a suppressive agent to the site of disease. Delivery is accomplished by introducing an expression vector encoding the suppressive agent into cells targeted for such sites, and administering the genetically modified cells to the patient. Suppressive agents of particular interest include IL-4; and anti-CD3 antibodies, particularly single chain anti-CD3 antibodies. Cells of interest for delivery include T cells and T cell hybridomas, where the T cell antigen receptor recognizes epitopes associated with the autoimmune disease. Alternatively, dendritic cells are used as delivery vectors.

Gene therapy for the prevention of autoimmune disease

Isolated nucleic acid compositions and sequences of anergy associated genes are provided, including the novel GRAIL gene. Expression of these genes is upregulated during the early stages of induction of anergy. The murine GRAIL sequence is shown to attenuate IL-2 transcription in T cells during response to antigenic stimulation. The identification of genes involved in the induction of anergy is useful in the evaluation of the pathophysiology or immunotherapy of cancer, autoimmune disease, and transplant rejection. Genetic sequences involved in anergy induction are useful markers in the evaluation of specific immunotherapies. Functional characterization of genes involved in anergy induction allows the elucidation of the mechanism(s) of T cell anergy, including the transcriptional blockade of IL-2, which may be manipulated to regulate T cell responses in human disease. The signaling pathways involving GRAIL are of significant interest in the identification of drugs that either block or upregulate the function(s) of GRAIL.

Anergy associated genes

Methods and compositions are provided for identifying genes associated with induction of anergy in T-cells and the use of the nucleic acids or proteins as diagnostics for monitoring induction of tolerance for the presence of tolerized T-cells in a physiological sample, or elucidating the pathway to anergy or activation in T-cells. A cysteine string protein is found to indicate quiescent T-cells and is lost with anergic T-cells.

Anergy genes

A method of selectively suppressing the immune system and conferring immunotolerance against a specific antigen by interferring with the L3T4 differentiation antigens on helper T cells is described. Simultaneous administration of a binding moiety specific for the L3T4-equivalent in the subject species and a specific antigen or administration of the antigen subsequent to the binding moiety for L3T4-equivalent within the time required for T-cell recovery results in a diminished ability of the subject to respond immunologically to the antigen, whether or not the subject has been exposed previously to the antigen.

Method of conferring immuno-tolerance to a specific antigen

A method of selectively suppressing the immune system and conferring immunotolerance against a specific antigen by interferring with the L3T4 differentiation antigens on helper T cells is described. Simultaneous administration of a binding moiety specific for the L3T4-equivalent in the subject species and a specific antigen results in a diminished ability of the subject to respond immunologically to the antigen, whether or not the subject has been exposed previously to the antigen.

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Portola Valley, CA, United States of America

C Garrison Fathman