The invention features multi-specific fusion protein complexes with one domain comprising IL-15 or a functional variant and a binding domain specific to IL-12 or IL-18.

The present invention includes compositions and methods for making and using the next generation of activatable pro-cytokine drugs by using a single-chain fragment crystallizable (Fc) region. This single-chain Fc fusion protein is engineered according to the formulas: P1-L-Fc-L-P2-L-Fc, or P1-L-Fc-L-P2-L-Fc-L-P3 in a linear sequence from amino- to carboxy-terminus, wherein protein (P) is the biologically active moiety, e.g., an antibody, or an antigen-binding fragment, or a cytokine receptor, or a cytokine, or a fusion protein consisting of above-mentioned components; L is optional and a protease cleavable, or non-cleavable linker (up to 50-mers amino acids) that is processed by enzymes enriched in tumor tissues, wherein P1, P2, and P3 are different biologically active moieties, but at least one of them is a cytokine that forms an intramolecular heterodimer. Processing the cleavable linker by tumor-specific enzymes serves as a switch to activate the cytokine in the tumor microenvironment.

A recombinant vaccinia virus containing a gene encoding sPD-1 or hyaluronidase and a pharmaceutical composition including the same are disclosed. The recombinant vaccinia virus containing a cancer therapy gene and having suppressed expression of K3L, TK, or VGF gene of the vaccinia virus has an excellent anti-tumor effect. Therefore, the recombinant vaccinia virus of the present invention can be advantageously used in cancer treatment.

The present invention provides Fc-fused protein constructs, which as monovalent dimers have a higher serum half-life compared to a native/natural molecule, and are, therefore, advantageous for achieving higher titers of the proteins during production, higher stability during storage, and improved efficacy when used as a therapeutic. Also provided are Fc-fused protein constructs having mutations in the Fc region that reduce effector functions, which have increased activity to inhibit tumor growth and are, therefore, advantageous when used as a cancer therapy.

The present invention relates to engineered a cytolytic immune cell comprising: i) a releasable protein which comprises a polypeptide of interest (POI) and a first interaction domain; and ii) a retention protein which is retained within an intracellular compartment of the cell and comprises a second interaction domain which binds to the first protein interaction domain, wherein binding between the first protein interaction domain and second protein interaction domain is disrupted by the presence of an agent, such that in the absence of the agent, the first protein interaction domain and second protein interaction domain bind and result in retention of the POI within an intracellular compartment; whereas in the presence of the agent, the first protein interaction domain and second protein interaction do not bind and the POI is released from the intracellular compartment and expressed at the cell surface or secreted by the cell.

The present invention provides biocircuit systems, effector modules and compositions for cancer immunotherapy. Methods for inducing anti-cancer immune responses in a subject are also provided.

Provided are anti-glypican-3 (GPC3) antibodies or antigen binding fragments thereof, and a chimeric antigen receptor (CAR) that binds glypican-3 (GPC3) containing an anti-GPC3 antibody in an extracellular domain, a transmembrane domain, and an intracellular signaling domain. Immune effector cells transduced with the disclosed CAR constructs can be used for cancer immunotherapy.

The disclosure provides urokinase plasminogen activator receptor (uPAR) binding polypeptides (e.g., uPAR antigen binding proteins), and fusion proteins comprising said uPAR binding polypeptides and a cytokine or variant thereof. The disclosure further provides pharmaceutical compositions comprising the uPAR binding polypeptides and fusion proteins of the disclosure and methods of treating cancer with the same. The disclosure further provides engineered IL-12 p35 and p40 polypeptides.

The disclosure features methods for treating cancer, including solid tumors and disseminated cancers such as myeloid malignancies, using one or more mRNAs encoding an OX40L polypeptide, an IL-12 polypeptide, an IL-15 polypeptide, and combinations thereof.

Provided herein are multi-chain chimeric polypeptides that include:

(a) a first chimeric polypeptide including a first target-binding domain, a soluble tissue factor domain, and a first domain of a pair of affinity domains; and (b) a second chimeric polypeptide including a second domain of a pair of affinity domains and a second target-binding domain, where the first chimeric polypeptide and the second chimeric polypeptide associate through the binding of the first domain and the second domain of the pair of affinity domains. Also provided here are methods of using these multi-chain chimeric polypeptides and nucleic acids encoding these multi-chain chimeric polypeptides.