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

Abstract: Compositions and methods are provided for the development and screening of antibody-based binding regions (ABR) that mimic T cell receptor specificity (TCRm). The TCRm-ABR of the disclosure are developed to specifically bind to the combination of an MHC antigen and peptide, and to substantially lack binding to the MHC in the absence of the cognate antigen.

Abstract: Provided herein are Receptor Elimination by E3 Ubiquitin Ligase Recruitment (REULR) constructs and related compositions, kits, methods of use and methods of production. REULR constructs comprise a variable domain heavy chain antibody (VHH) specific for a E3 Ubiquitin Ligase, and a VHH specific for a target protein, where in the E3 Ubiquitin Ligase and the target protein are different. REULR constructs described here target proteins associated with many maladies, but especially cancer.

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

Abstract: 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.

Abstract: Engineered synthekines and methods of use thereof are provided.

Abstract: 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.

Abstract: Variant IL-13 polypeptides are provided, which are engineered to have one or more of the following properties: (a) altered affinity for IL-13R?2, relative to the native human IL-13 protein; (b) altered affinity for IL-13R?1 relative to the native human IL-13 protein; (c) a disruption in the binding site for IL-4R? relative to the native human IL-13 protein.

Abstract: 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.

Abstract: 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.

Abstract: De novo designed polypeptides that bind to IL-2 receptor ??c heterodimer (IL-2R??c), IL-4 receptor ??c heterodimer (IL-4R??c), or IL-13 receptor ? subunit (IL-13R?) are disclosed, as are methods for using and designing the polypeptides.

Abstract: 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.

Abstract: The present disclosure relates generally to compositions and methods for modulating cell surface receptor signaling by specifically recruiting membrane phosphatases, in cis, to a spatial proximity of a natural killer cell receptor (NKR) molecule. More particularly, the disclosure provides novel multivalent protein-binding molecules that specifically bind NKR and antagonize the NKR-mediated signaling through recruitment of a phosphatase activity to dephosphorylate the intracellular domain of the NKR. Also provided are compositions and methods useful for producing such molecules, as well as methods for the treatment of health conditions associated with the inhibition of signal transduction mediated by NKRs.

Abstract: The present disclosure provides methods of producing a modified immune cell responsive to orthogonal cytokine signaling and a modified immune cell produced by said method. The present disclosure further provides a modified immune cell responsive to orthogonal cytokine signaling and methods for treating cancer comprising the modified immune cell.

Abstract: 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.

Abstract: 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.

Abstract: The present disclosure relates generally to compositions and methods for modulating cell surface receptor signaling by specifically recruiting membrane phosphatases, in cis, to a spatial proximity of a signal regulatory protein ? (SIRP?) molecule. More particularly, the disclosure provides novel multivalent protein-binding molecules that specifically bind SIRP? and antagonize the SIRP?-mediated signaling through recruitment of a phosphatase activity to dephosphorylate the intracellular domain of SIRP?. Also provided are compositions and methods useful for producing such molecules, methods for promoting maturation dendritic cells and for production of vaccine, as well as methods for the prevention and/or treatment of health conditions associated with the inhibition of signal transduction mediated by SIRP? and/or CD47.

Abstract: The present disclosure provides chimeric cytokine receptors comprising an intracellular signaling domain of an interleukin-9 receptor alpha (IL9Ra). The present disclosure also provides modified cell(s), i.e., immune cell(s) or precursor cell(s) thereof, wherein the cell(s) are engineered to express a) interleukin-9 receptor alpha (IL9Ra), or a chimeric cytokine receptor disclosed herein; and b) a chimeric antigen receptor (CAR). The present disclosure further provides a vector (e.g., an oncolytic adenoviral vector) comprising a nucleic acid sequence encoding a cytokine, as well as methods of using the modified cells and the vector for treating cancer in a subject in need thereof. Also provided are modified immune cell(s) or precursor cell(s) thereof which are engineered to express a chimeric antigen receptor (CAR), wherein expression of Cullin 5 in the cell(s) is reduced and/or eliminated. Also provided are methods and uses of the modified cells, e.g., for treating at least one sign and/or symptom of cancer.

Abstract: The present disclosure relates generally to compositions and methods for modulating signal transduction mediated by interleukin-12 and interleukin-23. In particular, the disclosure provides novel variants of interleukin-12 subunit p40 with reduced binding affinity to IL-12R?1. Also provided are compositions and methods useful for producing such IL-12p40 polypeptide variants, as well as methods for modulating IL-12p40-mediated signaling, and/or for the treatment of conditions associated with perturbations of signal transduction mediated by IL-12p40.

Abstract: The present disclosure relates generally to compositions and methods for modulating signal transduction mediated by interleukin-10 (IL-10). In particular, the disclosure provides novel IL-10 polypeptide variants with altered binding affinity to interleukin-10 receptor subunit beta (IL-10R?). Also provided are compositions and methods useful for producing such IL-10 polypeptide variants, as well as methods for modulating IL-10-mediated signaling, and/or for the treatment of conditions associated with the perturbation of signal transduction mediated by IL-10.