The present invention is directed to novel PD-1-targeted IL-15/Rα-Fc fusion proteins comprising an IL-15/IL-15Rα Fc-fusion protein and a PD-1 antigen binding domain. The PD-1-targeted IL-15/Rα-Fc fusion proteins can be administered to a patient to treat cancer.

Provided herein are multi-chain chimeric polypeptides that include: (a) a first chimeric polypeptide including a first target-binding domain, a soluble tissue factor domain, and a first domain of a pair of affinity domains; and (b) a second chimeric polypeptide including a second domain of a pair of affinity domains and a second target-binding domain, where the first chimeric polypeptide and the second chimeric polypeptide associate through the binding of the first domain and the second domain of the pair of affinity domains. Also provided here are methods of using these multi-chain chimeric polypeptides and nucleic acids encoding these multi-chain chimeric polypeptides.

Provided are chimeric cytokine modified antibodies containing an ultralong CDR3, such as based on a bovine antibody sequence or a humanized sequence thereof, in which a portion of the CDR3 of the heavy chain is replaced by an interleukin (IL-15) or IL-2, and related antibodies. Among provided antibodies are chimeric IL-15 cytokine modified antibody molecules that are further linked or complexed with an extracellular portion of the IL15Rα, such as the IL15Rα sushi domain. Also provided are methods of making and using the chimeric cytokine modified antibodies.

The present invention is directed to a fusion polypeptide, the polypeptide comprising: a. an interleukin-15 (IL-15); and b. an IL-15 activity-promoting sequence, wherein said sequence: is between 10 and 60 amino acid residues in length; and increases CD8+ T-cell proliferation 5 by the IL-15. Also provided are nucleic acids encoding the fusion polypeptide, associated methods of producing the fusion polypeptide, pharmaceutical compositions and kits comprising the same, and therapeutic uses thereof.

This disclosure provides a multimeric binding molecule, e.g., an IgM, IgM-like, IgA, or IgA-like binding molecule, e.g., an antibody with enhanced selectivity for cells expressing a target antigen at high density, e.g., tumor cells. Enhanced selectivity can be achieved, e.g., through modulation of binding affinity for the target antigen and/or through adjusting avidity via multimeric antigen binding.

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.

Genetically modified non-human animals comprising a humanized interleukin-15 (IL-15) gene. Cells, embryos, and non-human animals comprising a human IL-15 gene. Rodents that express humanized or human IL-15 protein.

The present invention is directed to novel targeted heterodimeric fusion proteins comprising an IL-15/IL-15Rα Fc-fusion protein and a TIM-3 antibody fragment-Fc fusion protein.

Described and provided herein are novel antibodies for Claudin 18.2. Also described and provided are pharmaceutical compositions of the antibodies and methods of use for the treatment of cancer.

The present invention is directed to novel PD-1 targeted heterodimeric Fc fusion proteins comprising an IL-15/IL-15Rα Fc-fusion protein and a PD-1 antibody fragment-Fc fusion protein. In some embodiments, the PD-1 targeted IL-15/Rα-Fc fusion proteins are administered to a patient to treat cancer. In some embodiments, the PD-1 targeted IL-15/Rα-Fc fusion proteins are administered in combination with a PD-1 blockade antibody such as nivolumab and/or pembrolizumab. In some embodiments, the PD-1 targeted IL-15/Rα-Fc fusion proteins do not compete with a PD-1 blockade antibody such as nivolumab and/or pembrolizumab for antigen binding.