The present invention relates to particularly stable and soluble scFv antibodies and Fab fragments specific for TNF, which comprise specific light chain and heavy chain sequences that are optimized for stability, solubility, in vitro and in vivo binding of TNF, and low immunogenicity. The antibodies are designed for the diagnosis and/or treatment of TNF-mediated disorders. The nucleic acids, vectors and host cells for expression of the recombinant antibodies of the invention, methods for isolating them and the use of the antibodies in medicine are also described.

The present disclosure provides compositions and methods for promoting stem cell and/or progenitor cell proliferation and/or differentiation. The provided compositions may be useful in treating a disease or condition that is related to mucosal barrier function, e.g., wound healing, treating skin conditions (e.g., atopic dermatitis, psoriasis, bed sores, or condition related to the aging of skin), treating a lung disorders (e.g., asthma), a condition related to improving mucosal barrier function, and/or treating injury to GI mucosa in a subject in need thereof. The present disclosure also provides methods for promoting the proliferation and/or differentiation of stem cells and/or the progenitor cells in a subject in need of such treatment by administering a composition. The ability to stimulate the proliferation and/or differentiation of stem cells and/or the progenitor cells in vivo, ex vivo and/or in vitro provides tremendous benefit. The present disclosure can be used to increase stem cell populations in in vivo, ex vivo and/or in vitro. Stem cell transplantation provides treatments and/or cures of many disease states, degeneration and/or injury.

Described herein are methods for producing and utilizing an alternative signal 1 domain to construct an optimally signaling CAR. Alternative signal 1 domains of the present technology are based on alternatives to CD3ζ, including mutated ITAMs from CD3ζ (which contains 3 IT AM motifs), truncations of CD3ζ, and alternative splice variants known as CD3s, CD3 theta, and artificial constructs engineered to express fusions between CD3s or CD30 and CD3ζ. CAR polypeptides comprising alternative signal 1 domains are utilized to engineer CAR T cells. Further, this technology related to methods of treating cancer by administering to a subject in need thereof CAR T cells comprising alternative signal 1 domains.

Described herein are methods for producing and utilizing an alternative signal 1 domain to construct an optimally signaling CAR. Alternative signal 1 domains of the present technology are based on alternatives to CD3ζ, including mutated ITAMs from CD3ζ (which contains 3 IT AM motifs), truncations of CD3ζ, and alternative splice variants known as CD3s, CD3 theta, and artificial constructs engineered to express fusions between CD3s or CD30 and CD3ζ. CAR polypeptides comprising alternative signal 1 domains are utilized to engineer CAR T cells. Further, this technology related to methods of treating cancer by administering to a subject in need thereof CAR T cells comprising alternative signal 1 domains.

Described herein are compositions and techniques related to generation and therapeutic application of artificial synapses. Artificial synapses are engineered extracellular vesicles, including exosomes, which incorporate sticky binders on their surface to anchor signaling domains against biological targets, such as receptors. These engineered additives can be organized in genetic vector constructs, expressed in mammalian cells, wherein the sticky binders attach to extracellular vesicles such as exosomes, thereby presenting their joined signaling domains which are rapidly taken up by recipient cells. Artificial synapses adopt the hallmark biophysical and biochemical features of extracellular vesicles, allowing for rapid deployment and scale-up. Importantly, this strategy can allow for kinetically favorable signal generation and signal propagation. This includes, for example, increasing density of agonist presentation to support receptor clustering—an onerous barrier for traditional receptor targeting strategies.

Described herein are compositions and techniques related to generation and therapeutic application of artificial synapses. Artificial synapses are engineered extracellular vesicles, including exosomes, which incorporate sticky binders on their surface to anchor signaling domains against biological targets, such as receptors. These engineered additives can be organized in genetic vector constructs, expressed in mammalian cells, wherein the sticky binders attach to extracellular vesicles such as exosomes, thereby presenting their joined signaling domains which are rapidly taken up by recipient cells. Artificial synapses adopt the hallmark biophysical and biochemical features of extracellular vesicles, allowing for rapid deployment and scale-up. Importantly, this strategy can allow for kinetically favorable signal generation and signal propagation. This includes, for example, increasing density of agonist presentation to support receptor clustering—an onerous barrier for traditional receptor targeting strategies.

The present invention relates to a compound of Formula (I)/(II) or pharmaceutically acceptable salts thereof. In Formula (I), Rh, Rg, Rf, m, Re, Rd, Ra, Rb, and Rc are as defined in the description. The present invention further relates to a pharmaceutical composition comprising the compound of Formula (I)/(II) or pharmaceutically acceptable salts thereof, and use of the compound of Formula (I)/(II) or the pharmaceutical composition in the manufacture of a medicament for treating inflammations such as rheumatoid arthritis. ##STR00001##

The present invention relates to a compound of Formula (I)/(II) or pharmaceutically acceptable salts thereof. In Formula (I), Rh, Rg, Rf, m, Re, Rd, Ra, Rb, and Rc are as defined in the description. The present invention further relates to a pharmaceutical composition comprising the compound of Formula (I)/(II) or pharmaceutically acceptable salts thereof, and use of the compound of Formula (I)/(II) or the pharmaceutical composition in the manufacture of a medicament for treating inflammations such as rheumatoid arthritis. ##STR00001##

The present invention relates to sustained-release formulations and dosage forms of ruxolitinib, or a pharmaceutically acceptable salt thereof, which are useful in the treatment of Janus kinase-associated diseases such as myeloproliferative disorders.

Genetically engineered bacteria, pharmaceutical compositions thereof, and methods of treating or preventing autoimmune disorders, inhibiting inflammatory mechanisms in the gut, and/or tightening gut mucosal barrier function are disclosed.