The present disclosure provides novel and improved IL-15 fusion proteins for use in the treatment of cancer and other disorders. In various embodiments, the fusion proteins of the invention have two functional domains: an IL-15/IL-15RαSushi domain (also referred to herein as an “IL-15/IL-15RαSushi complex”) and an antibody domain, each of which can take different forms, and configured such that the IL-15 is fused to the C-terminal of the antibody domain and co-expressed and non-covalently complexed with IL-15RαSushi. Importantly, the fusions proteins of the present invention address several of the limitations observed with the IL-15 therapeutics evaluated to date; specifically, the fusion proteins demonstrate extended the half-life of IL-15 in vivo, and demonstrate optimized preclinical activity compared to rIL-15 or related cytokine therapeutics.

This disclosure describes genetically engineered natural killer (NK) cells, pharmaceutical compositions that include these NK cells, and methods of making and using these NK cells.

Provided are compositions comprising an activatable proprotein comprising a first IL-15 or a variant thereof and a second IL-15Rα or variant thereof fused to a masking moiety comprising an antibody Fc region, and methods of using the same for cancer immunotherapy and other therapies.

The invention pertains to antibodies or other antigen binding proteins targeting the CD276 antigen, also known as B7-H3. The invention provides an improved set of antibodies which bind at new positions within the CD276 antigen and are of particular use as therapeutics in the treatment of CD276 positive cancer. Further the invention provides antibody conjugate and bispecific antibodies which were developed on basis of the novel anti-CD276 antibodies of the invention. Furthermore, the invention discloses the therapeutic use of the antibodies and other modulators in the treatment of CD276 positive cancer. Finally, the nucleic acid constructs encoding the molecules of the invention, recombinant cells expressing them, as well as particular uses and methods are provided.

The present invention relates to an immunocytokine comprising an heterodimeric protein complex based on IL-15/IL-15Rα, and to use thereof as a therapeutic agent, in particular as an agent for the treatment of cancer and an autoimmune disease. The present invention further relates to an immunocytokine comprising a heterodimeric protein complex based on an IL-15/IL-15Rα and an immunomodulatory antibody, and to use thereof as a therapeutic agent, in particular as an agent for the treatment of cancer and an autoimmune disease.

The present invention relates to, inter alia, an engineered cell (e.g., iPSC, IPS-derived NK, or NK cell) comprising a disrupted B2M gene and an inserted polynucleotide encoding one or more of SERPINB9, a fusion of IL15 and IL15Rα, and/or HLA-E. The engineered cell can further comprise a disrupted CIITA gene and an inserted polynucleotide encoding a CAR, wherein the CAR can be an anti-BCMA CAR or an anti-CD30 CAR. The engineered cell may further comprise a disrupted ADAM17 gene, a disrupted FAS gene, a disrupted CISH gene, and/or a disrupted REGNASE-1 gene. Methods for producing the engineered cells are also provided, and therapeutic uses of the engineered cells are also described. Guide RNA sequences targeting described target sequences are also described.

Provided herein are chimeric transmembrane proteins and proteins, nucleic acids encoding these chimeric transmembrane proteins or proteins, and mammalian cells containing these nucleic acids, and methods of making and using these mammalian cells.

The invention features combination therapies using an IL-15-based superagonist complex and an antibody to effectively treat subjects with cancer and infectious diseases.

Disclosed herein are compositions and methods for preparation and use of protein therapeutics, and more particularly protein clusters or backpacks having a plurality of therapeutic protein monomers reversibly crossed-linked by biodegradable linkers.

Provided herein are cytokines or functional fragments thereof that, in some embodiments, are engineered to be masked by a masking moiety at one or more receptor binding site(s) of the cytokine or functional fragment thereof. In some embodiments, the cytokines are engineered to be activatable by a protease at a target site, such as in a tumor microenvironment, by including a proteolytically cleavable linker. In some embodiments, the proteolytically cleavable linker links the cytokine to the masking moiety, links the cytokine to a half-life extension domain, and/or links the masking moiety to a half-life extension domain. The masking moiety blocks, occludes, inhibits (e.g., decreases) or otherwise prevents (e.g., masks) the activity or binding of the cytokine to its cognate receptor or protein. Upon proteolytic cleavage of the cleavable linker at the target site, the cytokine becomes activated, which renders it capable of binding to its cognate receptor or protein with increased affinity.