Cell-targeted serine protease constructs are provided. Such constructs can be used in methods for targeted cell killing such as for treatment cell of proliferative diseases (e.g., cancer). In some aspects, recombinant serine proteases, such as Granzyme B polypeptides, are provided that exhibit improved stability and cell toxicity. Methods and compositions for treating lapatinib or trastuzumab-resistant cancers are also provided.

The present invention addresses the problem of providing: a fusion protein or conjugated protein having excellent cell membrane permeability, containing a partial peptide derived from human, and suitable for intracellular delivery; an intracellular delivery carrier comprising such a fusion protein or conjugated protein; a partial peptide; a cell membrane permeation enhancer comprising the partial peptide; DNA; and a vector. The fusion protein or conjugated protein has a partial peptide comprising at least seven consecutive amino acid residues of an amino acid sequence encoded by a predetermined DNA, and a ligand directly or indirectly bound to the partial peptide and having the capability of binding to cell surfaces. The ligand is preferably an antibody. The intracellular delivery carrier comprises the fusion protein or conjugated protein. The cell membrane permeation enhancer comprises the partial peptide.

The invention provides compositions and methods for treating diseases associated with expression of a cancer associated antigen as described herein. The invention also relates to chimeric antigen receptor (CAR) specific to a cancer associated antigen as described herein, vectors encoding the same, and recombinant T cells comprising the CARs of the present invention. The invention also includes methods of administering a genetically modified T cell expressing a CAR that comprises an antigen binding domain that binds to a cancer associated antigen as described herein. The CAR may comprise a mutant CD28 costimulatory domain.

The present invention relates to a new antibody or an antigen binding fragment thereof for use in the treatment of cancer by targeting a B cell malignancy, a chimeric antigen receptor comprising the same, and a use of the same. The antibody of the present invention is an antibody for specifically binding to CD19 that is highly expressed in cancer cells (particularly, blood cancer), has very low homology to a CDR sequence thereof compared to a CDR sequence of a conventional CD19 target antibody so that the sequence thereof is unique, and specifically binds to an epitope that is different from a FMC63 antibody fragment binding to CD19 of the conventional art. A cell expressing the chimeric antigen receptor comprising an anti-CD19 antibody or the antigen binding fragment of the present invention induces immune cell activity in response to a positive cell line expressing CD19.

Provided herein is a composition comprising a fusion protein or a fragment or a variant thereof comprising an anti-PD1 antibody or a fragment/variant thereof and a TGF-β trap. Provided herein is a composition comprising a fusion protein or a fragment thereof or a variant thereof comprising an anti-PD1 antibody or a fragment/variant thereof and a ADA2 polypeptide. Also provided herein are methods of using the composition in treating cancer.

The present disclosure relates to tunable biocircuit systems for the development of controlled and/or regulated therapeutic systems. In particular, regulatable biocircuits containing destabilizing domains (DD) derived from mutant human cGMP-specific phosphodiesterase type 5 (PDE5) are disclosed. Especially, the present disclosure provides an effector module. Such effector module may include (a) a stimulus response element (SRE), wherein the SRE is a DD, said DD comprising at least one mutation relative to cGMP-specific 3′,5′-cyclic phosphodiesterase (hPDE5; SEQ ID NO: 1) and (b) at least one payload, which is attached, appended or associated with said SRE. The SRE may be responsive to one or more stimuli.

The present invention provides compounds and compositions for use in the treatment of cancer as part of a Chimeric Antigen Receptor T-cell (CAR-T) therapy. In particular, the present invention discloses IL-18 binding molecules such as, for example, the IL-18 binding protein (IL-18BP) for use in Chimeric Antigen Receptor T-cell (CAR-T) therapy as a modulator to avoid or minimize side effects.

The presently disclosed subject matter provides methods and compositions for enhancing the immune response toward tumor and pathogen antigens. It relates to immunoresponsive cells comprising two or more chimeric antigen receptors (CARs), wherein the CARs comprise different intracellular signaling domains, in particular, the intracellular signaling domains of the CARs comprise different co-stimulatory molecules.

The present invention includes compositions and methods that utilize a Universal Immune Receptor (UnivIR) CAR system comprising a modified T cell comprising a DOTA CAR and a DOTA-conjugated targeting ligand. In certain embodiments, the invention includes methods for treating, ameliorating, and/or preventing cancer. In certain embodiments, the invention provides a set of complementary molecular imaging tools that is applicable to CAR T cell therapy.

The present disclosure provides fusion proteins with improved signaling properties. Disclosed embodiments include fusion proteins that comprise an extracellular component comprising a target-binding domain, a transmembrane domain, and an intracellular component comprising a SH2 domain or a functional portion or variant thereof, and have improved signaling in response to antigen-binding, including of solid-tumor antigens with low levels of expression. Recombinant host cells expressing the fusion proteins, and polynucleotides encoding the fusion proteins, are also provided, as are compositions and methods comprising the same.