The present disclosure provides T-cell modulatory multimeric polypeptides (T-Cell-MMP) and their epitope conjugates comprising at least one immunomodulatory polypeptide (“MOD”) that may be selected to exhibit reduced binding affinity to a cognate co-immunomodulatory polypeptide (“Co-MOD”). The epitope may be, for example, a cancer-associated epitope, an infectious disease-associated epitope, or a self-epitope. The T-Cell-MMP-epitope conjugates are useful for modulating the activity of a T-cell by delivering immunomodulatory peptides, such as IL-2 or IL-2 variants that exhibit reduced binding affinity for the IL-2R, to T-cells in an epitope selective/specific manner, and accordingly, for treating individuals with a cancer, infectious disease or autoimmune disorder.

Provided herein are a fusion protein comprising first and second cytokine domains, and a half-life extension domain; and a pharmaceutical composition thereof. Also provided herein are methods of their use for treating, preventing, or ameliorating one or more symptoms of a proliferative disease.

Several embodiments disclosed herein relate to the compositions comprising engineered Natural Killer (NK) cells that express a chimeric receptor, the chimeric receptor imparting to the NK cells an enhanced ability to target specific cells, such as cancerous cells or those affected by an infectious disease. Several embodiments relate to NK cells that target cells expressing natural ligands of NKG2D, where the NK cells comprise transmembrane and/or signaling domains that lead to cytotoxic and/or cytolytic effects when the NK cells bind a target cell. Uses of NK cell compositions to treat diseases are also provided for in several embodiments.

Provided herein are IL-21 muteins and fusion proteins comprising the same for use in methods of treating a disease. Related conjugates, nucleic acids, vectors, host cells, pharmaceutical compositions and kits are also provided herein. Methods of making the IL-21 muteins and fusion proteins comprising the same, as well as methods of treating a subject in need thereof, are provided by the present disclosure. Further provided are PD-1 antigen-binding proteins.

Provided herein are IL-21 muteins and fusion proteins comprising the same for use in methods of treating a disease. Related conjugates, nucleic acids, vectors, host cells, pharmaceutical compositions and kits are also provided herein. Methods of making the IL-21 muteins and fusion proteins comprising the same, as well as methods of treating a subject in need thereof, are provided by the present disclosure. Further provided are PD-1 antigen-binding proteins.

The invention discloses a fusion protein, a preparation method thereof and application thereof in preparing ophthalmic disease treatment, anti-inflammation and anti-tumor medicament, and belongs to the field of biopharmaceutical technology. The present invention uses a flexible (F) or rigid (R) linker to fuse two polypeptides to respectively obtain two bifunctional fusion proteins, namely two multi-functional fusion protein macromolecules obtained by linking antiangiogenesis polypeptides HM-3, interleukin 4 and immunoglobulin Fc fragments via an amino acid linker, which can improve drug efficacy, prolong half-life and enhance stability, has the characteristics of strong effect, low toxicity and the like, and can be used for the prevention and treatment of solid tumors and various types of inflammations and neovascular ophthalmic diseases. The fusion protein is expressed in a eukaryotic cell by a genetic engineering method and purified by affinity chromatography or the like.

Several embodiments disclosed herein relate to methods and compositions for enhanced expansion of NK cells in culture. In several embodiments, the methods utilize one or more soluble interleukins as culture media supplements at one or more time points during expansion of the NK cell, or other immune cell, the expansion employing a feeder cell population.

The present disclosure provides expression constructs designed to provide for stable and/or inducible, tightly controlled production of genetically encoded payloads from engineered cells. These cassettes allow cells to be engineered to express genetically encoded payloads despite epigenetic silencing. As such, provided herein are expression systems for use in methods to engineer cells using CRISPR dCas9-activator systems such that expression of genetically encoded payloads (e.g., therapeutic proteins) can be optimized to overcome epigenetic silencing. In addition, provided herein are engineered cells comprising the expression systems.

The present disclosure provides expression constructs designed to provide for stable and/or inducible, tightly controlled production of genetically encoded payloads from engineered cells. These cassettes allow cells to be engineered to express genetically encoded payloads despite epigenetic silencing. As such, provided herein are expression systems for use in methods to engineer cells using CRISPR dCas9-activator systems such that expression of genetically encoded payloads (e.g., therapeutic proteins) can be optimized to overcome epigenetic silencing. In addition, provided herein are engineered cells comprising the expression systems.

The invention relates to a collection of signature peptides representing at least 10 proteins for use in cancer diagnosis and/or prognosis, to an artificial protein comprising signature peptides representing at least 10 proteins and to a nucleic acid construct encoding for such an artificial protein. The invention further relates to a collection of at least 10 proteins for use in cancer diagnosis and/or prognosis. Additionally, the invention relates to a method for cancer diagnosis and/or prognosis comprising the step of analyzing at least 10 proteins in a urine sample of a subject. Finally, the invention relates to an immunoassay product comprising antibodies for detecting at least 10 proteins.