Leland Stanford Junior University

University of Washington

California Institute of Technology

University of California

Pfizer Corporation

Parker Institute for Cancer Immunotherapy

Fred Hutchinson Cancer Center

Kenan Christopher Garcia

David Baker

Aaron Michael Ring

Aron M Levin

Daniel Adriano Silva Manzano

Umut Ulge

Jamie Spangler

Carl Walkey

Shawn Yu

Juan Luis Mendoza

Ignacio Moraga Gonzalez

Irving L Weissman

David Baltimore

Kipp Andrew Weiskopf

Michael Thomas Bethune

Michael Edward Birnbaum

Jonathan Sockolosky

Paul Henry Bessette

Jeffrey A Bluestone

Isaac J Rondon

Natasha K Crellin

Lauren K Ely

Eleonora Trotta

Sean Parker

Vincent Christopher Luca

Lora Picton

Luke Dang

Irwin D Bernstein

Alfredo Quijano Rubio

Nan Guo Ring

Claudia Yvonne Janda

John Connolly

Michael Hollander

Caleb R Glassman

Yi Miao

Keunwan Park

Leon Lih-Ren Su

Brian Weitzner

Sonia S Majri

Chia Chi Ho

James Daniel Moody

Chris King

Disclosed herein are compositions and methods for modulating IFN-γ-mediated signaling by completely or partially agonizing the downstream signal transduction mediated through at least one of the IFN-γ receptors. More particularly, the disclosure provides novel IFN-γ polypeptide variants with reduced binding affinity to at least one of its receptors. The disclosure also provides compositions and methods useful for producing such molecules, as well as methods for the treatment of health diseases associated with the perturbation of signal transduction mediated by IFN-γ.

Interferon-gamma biased agonists

De novo designed polypeptides that bind to IL-2 receptor βheterodimer (IL-2Rβ), IL-4 receptor αheterodimer (IL-4Rα), or IL-13 receptor α subunit (IL-13Rα) are disclosed, as are methods for using and designing the polypeptides.

De novo design of potent and selective interleukin mimetics

De novo designed polypeptides that bind to IL-2 receptor βγheterodimer (IL-2Rβγ), IL-4 receptor αγheterodimer (IL-4Rαγ), or IL-13 receptor α subunit (IL-13Rα) are disclosed, as are methods for using and designing the polypeptides.

The present disclosure generally relates to, inter alia, a class of chimeric switch receptors containing an endodomain of an IL-9 receptor, engineered to modulate transcriptional regulation in a ligand-dependent manner. The disclosure also provides compositions and methods useful for producing such receptors, nucleic acids encoding same, host cells genetically modified with the nucleic acids, as well as methods for modulating gene expression, modulating an activity of a cell, and/or for the treatment of various health conditions or diseases.

Switch receptors using IL-9 signaling domains

High affinity SIRP-α reagent are provided, which (i) comprise at least one amino acid change relative to the wild-type protein; and (ii) have an increased affinity for CD47 relative to the wild-type protein. Compositions and methods are provided for modulating phagocytosis in a mammal by administering a therapeutic dose of a pharmaceutical composition comprising a high affinity SIRPα reagent, which blocks the physiological binding interaction between SIRPα and its ligand CD47.

High affinity SIRP-alpha reagents and methods of using

Provided herein, inter alia, are human interleukin-2 (IL-2) muteins or variants thereof. In particular, provided herein are IL-2 muteins that have a decreased binding capacity for IL-2Rγ. Such IL-2 muteins are useful, for example, as IL-2 partial agonist 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 autoimmune diseases or conditions). 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.

Partial agonists of interleukin-2

Wnt signaling antagonist and agonist compositions and methods for their use are provided.

Frizzled specific Wnt agonists and antagonists

Engineered orthogonal cytokine receptor/ligand pairs, and methods of use thereof, are provided.

Biologically relevant orthogonal cytokine/receptor pairs

Novel human interleukin-2 (IL-2) muteins or variants thereof, and nucleic acid molecules and variants thereof are provided. Methods for producing these muteins as well as methods for stimulating the immune system of an animal are also disclosed. In addition, the invention provides recombinant expression vectors comprising the nucleic acid molecules of this invention and host cells into which expression vectors have been introduced. Pharmaceutical compositions are included comprising a therapeutically effective amount of a human IL-2 mutein of the invention and a pharmaceutically acceptable carrier. The IL-2 muteins can be used in pharmaceutical compositions for use in treatment of cancer and in stimulating the immune response.

Superagonists and antagonists of interleukin-2

R-spondin (RSPO) surrogate compositions and methods for their use are provided. RSPO surrogates of the invention comprise (i) a specific binding domain for Ring Finger Protein 43 (RNF43) or Zinc and Ring Finger Protein 3 (ZNRF3) and (ii) a cell targeting domain More specifically, wherein the specific binding domain for RNF43 or ZNRF3 is an antibody fragment, and wherein the cell targeting domain is a cytokine.

Compositions comprising R-Spondin (RSPO) surrogate molecules

Variant IL-13 polypeptides are provided, which are engineered to have one or more of the following properties: (a) altered affinity for IL-13Rα2, relative to the native human IL-13 protein; (b) altered affinity for IL-13Rα1 relative to the native human IL-13 protein; (c) a disruption in the binding site for IL-4Rα relative to the native human IL-13 protein.

Therapeutic IL-13 polypeptides

Compositions and methods are provided for the identification of peptide sequences that are ligands for a T cell receptor (TCR) of interest, in a given MHC context.

Ligand discovery for T cell receptors

Engineered proteins, polynucleotides encoding such proteins, and methods of use thereof are provided, which engineered proteins enhance the sensitivity of a cell to IL-2.

Engineered proteins to enhance sensitivity of a cell to IL-2

De novo designed polypeptides that bind to IL-2 receptor &#x3b2;heterodimer (IL-2R&#x3b2;), IL-4 receptor &#x3b1;heterodimer (IL-4R&#x3b1;), or IL-13 receptor &#x3b1; subunit (IL-13R&#x3b1;) are disclosed, as are methods for using and designing the polypeptides.

The present invention provides antibodies, or antigen-binding portions thereof, which specifically bind to IL-2 and reduce the affinity of IL-2 binding to IL-2R&#x3b1; and IL-2R&#x3b2;. The invention further provides a method of obtaining such antibodies and nucleic acids encoding the same. The invention further relates to compositions and therapeutic methods for use of these antibodies for the treatment and/or prevention of autoimmune diseases, disorders or conditions and for immunosuppression, including, but not limited to, administering a complex comprising the antibody and IL-2.

Anti-IL-2 antibodies and compositions and uses thereof

Growing community of inventors

Menlo Park, CA, United States of America

Kenan Christopher Garcia