The present disclosure provides for proprotein and activatable proprotein compositions. A proprotein contains a functional protein (i.e. a full length protein or functional fragment thereof) which is coupled to a peptide mask that inhibits the binding of the functional protein to its target or binding partner. An activatable proprotein contains a functional protein coupled to a peptide mask, and further coupled to an activatable linker, wherein in an non-activated state, the peptide mask inhibits binding of the functional protein to its target or binding partner and in an activated state the peptide mask does not inhibit binding of the functional protein to its target or binding partner. Proproteins can provide for reduced toxicity and adverse side effects that could otherwise result from binding of a functional protein at non-treatment sites if it were not inhibited from binding its binding partner. Proproteins can further provide improved biodistribution characteristics. Proproteins containing a peptide mask can display a longer in vivo or serum half-life than the corresponding functional protein not containing a peptide mask. The disclosure further provides methods of screening for, making, and using these proproteins.

The present invention provides a chimeric molecule comprising a VWF protein fused to a heterologous moiety via a VWF linker. The invention provides an efficient VWF linker that can be cleaved in the presence of thrombin. The chimeric molecule can further comprise a polypeptide chain comprising a FVIII protein and a second heterologous moiety, wherein the chain comprising the VWF protein and the chain comprising the FVIII protein are associated with each other. The invention also includes nucleotides, vectors, host cells, methods of using the chimeric proteins.

An antigen-specific T cell binding agent is provided, where a multivalent spheromer system utilizes a scaffold of a self-assembling polypeptide nanoparticle, for example using selfassembling ferritin polypeptides. The system is compatible with current pMHC reagents, including both MHC-I and MHC-II molecules, and streptavidin reagents that allow ease-of-use. The spheromer assembly pipeline provides a consistent reagent across multiple batches of synthesis with ease of production. The defined geometry of the scaffold allows precise site-directed conjugation of pMHC, leading to a homogenous reagent. The spheromer binds cognate TCRs with a significantly higher avidity than a tetrameric reagent.

The invention is directed to cell-targeted cytotoxic agents, including sortase serine protease constructs. Methods for targeted cell killing for treatment of proliferative diseases, for example, cancer, are provided. Exemplary embodiments comprise an R-spondin ligand for targeting the cytotoxic agents to effect the cell killing.

Autoregulatory systems that have been implemented to control the expression and activity of Cast 3d, including the activity of Cast 3d in vivo, thereby reducing collateral damage in cells at off-target sites (e.g., non-target messenger RNA transcripts. The autoregulatory system is in the form of a nucleic acid molecule comprising a zinc finger binding site, a promoter, and a nucleotide sequence encoding a Cast 3d fusion protein, and a transcriptional repressor domain, and wherein the Cast 3d fusion protein binds to the zinc finger binding site and represses transcription of the nucleotide sequence encoding the Cast 3d fusion protein.

Provided herein are, inter alia, compositions and methods for demethylating and methylating a target DNA sequences in a mammalian cell. The compositions and methods are, inter alia, useful for modulating the expression of a target gene, or to create a gene regulatory network.

The present disclosure relates to pharmaceutical compositions comprising a non-naturally occurring fusion molecule and one or more pharmaceutically acceptable carriers, formulated for oral delivery to a subject, and designed to provide for improved, effective therapies for treatment of, e.g., inflammatory diseases, autoimmune diseases, cancer, metabolic disorders, and growth deficiency disorders.

Disclosed herein are conjugates including a fatty acid, a self-assembly domain, and a polypeptide, where the conjugates have phase transition behavior. Further disclosed are methods of using the conjugates to treat disease, methods of delivering an agent, and methods of preparing the conjugates.

Disclosed is a variant of a parent polypeptide including an Fc fragment, the variant having an improved half-life with respect to the parent polypeptide, and including at least one mutation of the Fc fragment increasing the binding of Fc to FcRn; and at least one mutation of the Fc fragment increasing the sialylation of Fc.

Compositions and methods relating to synthetic modification of histone-binding proteins. Some histone-binding fusion-protein compositions include a modified polycomb chromodomain (PCD) motif, for example two tandem copies of the H3K27me3-binding PCD at the N-terminus separated by a linker. Some methods relate to multivalent engagement of one or more histone proteins or to tuning the activity of a synthetic histone-binding transcriptional regulator, for example by contacting the one or more histone proteins with a histone-binding fusion-protein composition having a modified PCD motif.