The disclosure provides compositions and methods for inducing programmed cell death, such as necroptosis. Compositions may comprise fusion proteins comprising a death inducing domain and a multimerization domain; nucleic acids encoding fusion proteins; and cells comprising fusion proteins. The compositions may be used in methods such as cancer therapy, including in combination with additional immunotherapeutics.

Provided is a method for preparing a PD-1 gene-modified humanized animal model. The method utilizes the CRIPSR/Cas9 technique to replace partial fragments of a mouse PD-1 gene with fragments of a human PD-1 gene using homologous recombination by constructing a targeting vector, thereby preparing a gene-modified humanized mouse. This mouse can normally express a PD-1 protein containing the functional domain of the human PD-1 protein, and can be used as an animal model for mechanism research regarding PD-1, PD-L1 and other signals, for screening regulators, and for toxicological research. The method has an important and high application value in studies on functions of the PD-1 gene and in the development of new drugs.

This disclosure features structurally-stabilized and/or cysteine-reactive peptide inhibitors for selective targeting of BFL-1, or dual targeting of BFL-1 and MCL-1. Also disclosed are methods of using such structurally-stabilized and cysteine-reactive peptides in the treatment of BFL-1- and/or MCL-1-expressing or -dependent cancers or diseases of cellular excess (e.g., autoimmune or inflammatory conditions). Also provided are combination therapies comprising such structurally-stabilized and/or cysteine-reactive peptides and inhibitors of the DNA damage response pathway, such as an ATM kinase inhibitor, ATR kinase inhibitor, CHK1/2 inhibitor, or PARP inhibitor; or an inhibitor of MCL-1, or a selective inhibitor of BCL-2, or an inhibitor of BCL-2/BCL-XL, for the treatment of BFL-1-expressing or -dependent cancers (e.g., AML), BFL-1 and MCL-1-expressing or -dependent cancers, or diseases of cellular excess (e.g., autoimmune or inflammatory conditions).

Described herein are methods and compositions for the treatment of cancer. Aspects include administering (1) an agent that inhibits activity of a CBM signalosome complex, or (2) a cell engineered to have reduced CBM signalosome complex levels to a subject having cancer. In various embodiment, the methods further comprise administering second therapeutic, for example, a checkpoint inhibitor or anti-cancer therapy, to the subject.

Provided herein are compositions including peptide or nucleic acids encoding peptides and related methods for the treatment of angiogenic conditions such as cancer, vascular disorders such as cardiovascular disorders, and infectious disease.

The present disclosure relates to novel PD-1 decoy variants, compositions, and methods to confer and/or increase immune responses mediated by cellular immunotherapy, such as by adoptively transferring tumor-specific genetically-modified subsets of lymphocytes.

Compositions and methods of use thereof for delivering nucleic acid cargo into cells are provided. The compositions typically include (a) a 3E10 monoclonal antibody or an antigen binding, cell-penetrating fragment thereof; a monovalent, divalent, or multivalent single chain variable fragment (scFv); or a diabody; or humanized form or variant thereof, and (b) a nucleic acid cargo including, for example, a nucleic acid encoding a polypeptide, a functional nucleic acid, a nucleic acid encoding a functional nucleic acid, or a combination thereof. Elements (a) and (b) are typically non-covalently linked to form a complex.

The present disclosure relates to a method of identifying an agent-of-interest that alters binding or activity of a client protein to a chaperone, co-chaperone, or chaperone-co-chaperone complex, the method including: determining a three-dimensional (3D) structure of a client protein-of-interest; evaluating the 3D structure of the client protein-of-interest to identify an unstable substructure of the 3D structure of the client protein-of-interest; and determining an amino acid sequence of the unstable substructure of the 3D structure of the client protein-of-interest to identify an agent-of-interest that alters binding or activity of a client protein to a chaperone, co-chaperone, or chaperone-co-chaperone complex.

The present invention provides nucleic acid constructs, expression vectors, transgenic cell and methods of making and using the same, wherein the nucleic acid construct includes a synthetic promoter designed from the endogenous promoter of BIRC5 and LAMC2. In illustrative working embodiments of the invention, an exogenous nucleic acid fragment encoding thymidine kinase is operably linked to the synthetic promoter which is then shown to regulate the expression of this polypeptide.

The present invention relates to a ligand-binding molecule the ligand-binding activity of which is attenuated by the cleavage of a cleavage site, a method for producing the ligand-binding molecule, a complex formed by the ligand-binding molecule and a ligand, a fusion protein comprising the ligand-binding molecule and a ligand, and a pharmaceutical composition comprising the ligand-binding molecule or a fusion protein of the ligand-binding molecule and a ligand.