The Ohio State University

Pharmacyclics, Inc.

Immunomedics, Inc.

Hendrix College

Novartis Ag

University of Pennsylvania

John C Byrd

Natarajan Muthusamy

Amy Jo Johnson

Jason A Dubovsky

David M Goldenberg

Hans J Hansen

Ching-Shih Chen

David Miklos

Thomas E Goodwin

Danilo Perrotti

Erin Hertlein

Michael R Grever

David M Lucas

Ola Elgamal

Mouad Abdulrahim

Chad E Bennett

Sandip Madhukar Vibhute

Carl H June

James T Dalton

Tarak D Mody

Joseph J Buggy

Jennifer Brogdon

Saar Gill

David Jonathan Glass

Marcela V Maus

Joan Mannick

Leon Murphy

David L Porter

Anna Vulpetti

Marco Ruella

Dasheng Wang

Samuel K Kulp

Mariusz Wasik

Guido Marcucci

Daniela Angst

Saad Kenderian

William Raj Sellers

Betty Chang

Paolo Neviani

Jennifer A Woyach

Emilia Mahoney

Ramasamy Santhanam

Frank Frissora

Xiaobin Zhao

Qing Liu

Mark R Parthun

Joseph Fraietta

François Gessier

Disclosed herein are compounds, 3,4,6,8-substituted-2-([1,1'-biphenyl]-4-yl)quinoline analogs, that are inhibitors of dihydroorotate dehydrogenase (DHODH) with improved pharmacokinetic properties. The disclosed compounds can be used in the treatment of a variety of disorders and diseases in which inhibition of DHODH can be clinically useful, including cancer, such as a hematological cancer, including acute myeloid leukemia (AML); graft-versus-host-diseases; autoimmune disorders; and disorders associated with T-cell proliferation. The disclosed compounds can demonstrate flip-flop kinetics when administered orally, i.e., pharmacokinetics in which the rate of absorption, rather than the rate of elimination, dominates the pharmacokinetics. The disclosed compounds can demonstrate a sustained pharmacokinetic profile instead of an immediate release profile. This abstract is intended as a scanning tool for purposes of searching in the particular art and is not intended to be limiting of the present disclosure.

Methods and compositions for inhibition of dihydroorotate dehydrogenase

Disclosed herein are compounds, 3,4,6,8-substituted-2-([1'-biphenyl]-4-yl)quinoline analogs, that are inhibitors of dihydroorotate dehydrogenase (DHODH) with improved pharmacokinetic properties. The disclosed compounds can be used in the treatment of a variety of disorders and diseases in which inhibition of DHODH can be clinically useful, including cancer, such as a hematological cancer, including acute myeloid leukemia (AML); graft-versus-host-diseases; autoimmune disorders; and disorders associated with T-cell proliferation. The disclosed compounds can demonstrate flip-flop kinetics when administered orally, i.e., pharmacokinetics in which the rate of absorption, rather than the rate of elimination, dominates the pharmacokinetics. The disclosed compounds can demonstrate a sustained pharmacokinetic profile instead of an immediate release profile. This abstract is intended as a scanning tool for purposes of searching in the particular art and is not intended to be limiting of the present disclosure.

Described herein are methods for treating and preventing graft versus host disease using ACK inhibitors. The methods include administering to an individual in need thereof an ACK inhibitor such as ibrutinib for treating and preventing graft versus host disease.

Methods of treating and preventing graft versus host disease

The invention provides compositions and methods for treating diseases associated with expression of CD19, e.g., by administering a recombinant T cell comprising the CD19 CAR as described herein, in combination with a kinase inhibitor, e.g., a kinase inhibitor described herein. The invention also provides kits and compositions described herein.

Treatment of cancer using anti-CD19 Chimeric Antigen Receptor

Described herein is a mutation that confers resistance to the treatment with a BTK inhibitor. Described herein is a modified PLC&#x3b3;2 polypeptide that is modified at amino acid position 742, 845, or 1140 and the modified PLC&#x3b3;2 polypeptide exhibits decreased inhibition (e.g., resistance) to a covalent and/or irreversible BTK inhibitor. Described herein are diagnostic methods for detecting the modified polypeptide and nucleic acid encoding the modified polypeptide and applications of the methods thereof. Described herein are compositions, combinations, and kits containing the modified polypeptide and methods of using the modified polypeptide. Also described herein are methods of using the modified polypeptide as screening agents for the identification and design of inhibitors of PLC&#x3b3;2.

Phospholipase C gamma 2 and resistance associated mutations

Described herein are methods and compositions comprising a covalent TEC family kinase inhibitor for use in adjuvant therapy, including adjuvant cancer therapy, vaccination and treatment of immune disorders and pathogenic infections.

TEC family kinase inhibitor adjuvant therapy

A method of (a) treating a lymphoproliferative disease in a subject in need thereof; (b) slowing the progression of lymphoproliferative disease in a subject who has been diagnosed with a lymphoproliferative disease; or (c) preventing or delaying development of a lymphoproliferative disease in a subject who is at risk of developing a lymphoproliferative disease. The method generally comprises administering to the individual an effective amount of a combination therapy comprising: i) at least one autophagy modulating agent, or a derivative, pharmaceutically acceptable salt thereof, or prodrug thereof; and ii) at least one CDK inhibitor agent, or a derivative, pharmaceutically acceptable salt thereof, or prodrug thereof, wherein the i) agent and the ii) agents are administered in amounts sufficient to enhance the cytotoxicity of the combination relative to the CDK inhibitor agent treatment alone.

Compositions and methods for increasing drug efficacy in cancer

Disclosed are compositions that include anti-CD74 immunoconjugates and optionally a therapeutic and/or diagnostic agent. In preferred embodiments, the immunoconjugates comprise one or more anti-CD74 antibodies or antigen-binding fragments thereof, conjugated to a liposome or micelle. Also disclosed are methods for preparing the immunoconjugates and using the immunoconjugates in diagnostic and therapeutic procedures. In certain preferred embodiments, the therapeutic methods comprise administering to a subject with a CD74-expressing disease an anti-CD74 immunoconjugate and thereby inducing apoptosis of CD74-expressing cells. In more preferred embodiments, the CD74 immunoconjugate is capable of inducing cell death in the absence of any other therapeutic agent, although such agents may be optionally administered prior to, together with or subsequent to administration of the anti-CD74 immunoconjugate. The compositions may be part of a kit for administering the anti-CD74 immunoconjugates or compositions.

Anti-CD74 immunoconjugates and methods of use

The invention provides for methods of treating a mammal who has a BCR/ABL-mediated leukemia, including chronic myelogenous leukemia (CML), particularly the blast crisis stage of CML, Philadelphia-positive acute lymphoblastic leukemia (Ph'-ALL), and refractory leukemias. The invention also provides for compounds for the treatment of these leukemias and methods of identifying anti-leukemic agents.

Therapeutic agents for the treatment of leukemia

Methods&#x2014;for treatment and prevention of lymphoid malignancies, including, but not limited to acute lymphoblastic leukemia (ALL), chronic lymphocytic leukemia (CLL), B-cell lymphoma, Acute Myeloid leukemia (AML), and mantle cell lymphoma (MCL). The methods include administration of a therapeutically effective amount of FTY720 (2-Amino-2-[2-(4-octylphenyl)ethyl]propane 1,3-diol hydrochloride) or a derivative, pharmaceutically acceptable salt thereof, or a prodrug thereof to a subject.

Therapeutic agents for the treatment of lymphoid malignancies

A number of FTY720-derived compounds with antitumor activity are described. These compounds include the compounds of formula I: wherein Ris independently selected from the group consisting of hydrogen, methyl. methoxy, and hydroxyl; Ris independently selected from the group consisting of hydrogen, methoxy, and hydroxyl; Ris independently selected from the group consisting of alkyl and cyclo-alkyl; and n is independently selected from 0 to 6. The compounds have lower immunosuppressive side effects as a result of not being phosphorylated by sphingosine kinase 2.

FTY720-derived anticancer agents

Growing community of inventors

Columbus, OH, United States of America

John C Byrd