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.

This application discloses, inter alia, certain antibodies that specifically bind to human TREM2 (triggering receptor expressed on myeloid cells 2). In some embodiments, the antibodies act as TREM2 agonists. In some embodiments, antibodies herein specifically bind to the stalk region of intact, human TREM2, without binding to soluble TREM2, which is the product of TREM2 cleavage between residues H157 and S158. In some embodiments, the antibodies act as TREM2 agonists, specifically bind to the stalk region of TREM2 with dissociation constants ranging from 10 nM to as low as 100-500 pM, 10-50pM, or 1-10 pM, specifically bind to a TREM2 epitope spanning the H157-S158 cleavage site, and do not bind to soluble TREM2. In some embodiments, antibodies herein also inhibit shedding of soluble TREM2 in a human microglia cell model and in vivo in a mouse model, decrease levels of soluble TREM2 in plasma, CSF and/or the brain, enhance survival of human microglia cells, and increase Aβ plaque formation and compaction in a human microglia model (for example, as measured by increased Aβ plaque intensity and/or increased X04 plaque intensity in human microglia), and thus, may provide a number of neuroprotective activities.

The application provides anti-ROR1 monoclonal antibodies, antigen binding portions thereof, therapeutic compositions thereof and/or nucleic acid encoding the same, and their use to upregulate the function of T-cells to enhance cell-mediated immune responses in the treatment of cancer and other T-cell dysfunctional disorders.

A nucleic acid molecule comprising a nucleotide sequence encoding an inhibitory chimeric antigen receptor (iCAR) capable of preventing or attenuating undesired activation of an effector immune cell, wherein the iCAR comprises an extracellular domain that specifically binds to a single allelic variant of a polymorphic cell surface epitope absent from mammalian tumor cells due to loss of heterozygosity (LOH) but present at least on all cells of related mammalian normal tissue; and an intracellular domain comprising at least one signal transduction element that inhibits an effector immune cell is provided. Vectors and transduced effector immune cells comprising the nucleic acid molecule and methods for treatment of cancer comprising administering the transduced effector immune cells are further provided.

Antibodies that bind ICOS (Inducible T cell Co-Stimulator). Therapeutic use of anti-ICOS antibodies for modulating the ratio between regulatory T cells and effector T cells, to stimulate the immune system of patients, including use in treating cancers. Methods of producing anti-ICOS antibodies, including species cross-reactive antibodies, using transgenic knock-out mice.

The present invention relates to antibodies that bind to human CD137 and display agonist activity, and may be useful for treating solid and hematological tumors alone and in combination with chemotherapy and ionizing radiation.

The present invention provides pharmaceutical combinations comprising (a) a compound of formula (I) wherein R represents phenyl or pyridinyl; wherein phenyl is optionally substituted by one or two substituents independently selected from lower alkyl, lower alkoxy, hydroxyl, amino, lower alkylamino, lower dialkylamino, acetylamino, halogen and nitro; and wherein pyridinyl is optionally substituted by amino or halogen; R1 represents hydrogen or cyano-lower alkyl; and wherein the prefix lower denotes a radical having up to and including a maximum of 4 carbon atoms; or a pharmaceutically acceptable derivative thereof; and (b) a CD40 agonist.

##STR00001##

The present disclosure describes combination therapies and uses thereof for the treatment of cancer. The combinations therapies include at least a first therapeutic agent and a second therapeutic agent.

Provided are anti-tumor necrosis factor receptor 2 (TNFR2) antibodies and related compositions, which may be used in any of a variety of therapeutic or diagnostic methods, including the treatment or diagnosis of oncological diseases, inflammatory and/or autoimmune diseases, and others. In some embodiments, the isolated antibody, or antigen-binding fragment thereof, does not substantially bind to TNFR1, herpesvirus entry mediator (HVEM), CD40, death receptor 6 (DR6), and/or osteoprotegerin (OPG).

Fusion polypeptides including at least one Fc binding domain linked to at least one integrin binding domain are provided. In some embodiments, the at least one Fc binding domain is one or more Fc binding domains from Protein A, Protein G, or Protein Z and the at least one integrin binding domain comprises one or more fibronectin type III domains (for example repeats 12-14 of fibronectin type III domains and optionally the connecting segment of fibronectin). Protein complexes including the polypeptide and one or more antibodies are also provided. Methods of using the polypeptide and/or polypeptide:antibody complex are provided, including treating a subject with a tumor, inducing an immune response to a tumor, and/or targeting an antibody to a tumor cell.