Abstract: The invention relates to kinase inhibitors, in particular inhibitors of protein kinases including the SIK-family CSF1R, ABL/BCR-ABL, SRC, HCK, PDGFR, KIT and/or their mutants. Although structurally similar to dasatinib, the kinase inhibitors of the invention are distinctive; possessing a particular class of halogenated heteroaryls. Such kinase inhibitors can display one or more certain properties distinct to dasatinib and other structurally similar kinase inhibitors. The kinase inhibitors of the invention or pharmaceutical compositions comprising them may be used in the treatment of a disorder or condition, such as a proliferative disorder, for example, a leukaemia or solid tumour. In particular, these and other structurally similar kinase inhibitors may be used in the treatment of a proliferative disorder—such as a mixed phenotype acute leukaemia (MPAL)—characterised by (inter-alia) the presence of MEF2C protein, a human chromosomal translocation at 11q23, and/or a KMT2A fusion oncoprotein.

Abstract: The invention is based on the identification of the intracellular kinase calcium/calmodulin-dependent protein kinase 1D (CAMK1D) as a key checkpoint inhibitor in tumour cells mediating resistance against cytotoxic T lymphocytes (CTL). CAMK1D was identified in PD-L1 refractory tumours to impair CTL-induced death receptor signalling and apoptosis via caspase inhibition. The invention offers therapeutic approaches involving impairing CAMK1D immune checkpoint function by various CAMK1D inhibitors, especially nucleic acid or small molecule inhibitors of CAMK1D and/or treatments involving CAMK1D inhibitors with death receptor agonists. The medical approaches of the invention are useful for treating subjects suffering from various proliferative disorders; preferably such proliferative disorders that are characterized by a resistance to CTL mediated immune responses, or which are refractory or resistant to treatments with other immune checkpoint therapies, such as PD1-PDL1 antagonistic treatments.

Abstract: The invention is based on the surprising finding of antibodies that bind to an immunoglobulin-like (Ig) domain of the extra cellular domain (ECD) of IGSF11 (VSIG3) can also inhibit the interaction between IGSF11 and IGSF11 receptors such as VSIR (VISTA), the inhibition of such interaction can sensitise tumour cells to anti-tumour immune responses. In particular, the invention provides products, compositions and methods for treating diseases using modulators of IGSF11, especially antigen binding proteins targeting an Ig domain of IGSF11-ECD, including those being inhibitors of IGSF11-interaction with VSIR. Also provided are methods of sensitising cells involved with a proliferative disorder against the cytotoxic effect of cell-mediated immune responses, and/or to kill such cells and/or methods for treating proliferative diseases, using an IGSF11 inhibitor such as an antibody binding to an Ig domain of IGSF11-ECD, as well as certain related aspects including detection, diagnostic and screening methods.

Abstract: The invention is based on the surprising finding of antibodies that bind to IGSF11 (VSIG3) can also inhibit the interaction between IGSF11 and IGSF11 receptors such as VSIR(VISTA), the inhibition of such interaction can sensitise tumour cells to anti-tumour immune responses. In particular, the invention provides products, compositions and methods for treating diseases using modulators of IGSF11, especially antigen binding proteins targeting IGSF11, including those being inhibitors of IGSF11-interaction with VSIR. Also provided are methods of sensitising cells involved with a proliferative disorder against the cytotoxic effect of cell-mediated immune responses, and/or to kill such cells and/or methods for treating proliferative diseases, using an IGSF11 inhibitor such as an IGSF11-binding antibody, as well as certain related aspects including detection, diagnostic and screening methods.

Abstract: The invention is based on the surprising finding that SIK3 is associated with resistance against anti-tumour immune responses. In particular, the invention provides methods for treating proliferative diseases using inhibitors of SIK3, especially nucleic acid or small molecule inhibitors of SIK3. Also provided are methods of sensitising cells involved with a proliferative disorder against the cytotoxic effect of certain pro-inflammatory signalling pathways, and/or to kill such cells and/or methods for treating proliferative diseases, using a SIK3 inhibitor together with ligands or agonists of such signalling pathways.

Abstract: The present invention pertains to novel modulators of tumor resistance against T-cell mediated cytotoxic immune responses. The invention provides antagonists of tumor immune escape mechanisms and methods and other aspects related thereto, and therefore provides novel approaches for treating or aiding a treatment of various cancerous diseases and/or the diagnosis thereof. The invention pertains to both negative and positive regulators of tumor cell resistance and suggests the use inhibitors or activators of these genes for therapeutic purposes. In particular aspects, the invention provides combination therapeutics and/or therapies involving such inhibitors or activators. The invention furthermore provides screening methods for novel cancer therapeutics modulating the action of the identified genes, diagnostic approaches to detect cancer resistance to cytotoxic T-cells as well as pharmaceutical compositions and diagnostic kits, for use with or related to for performing these methods.

Abstract: The invention provides antigen binding proteins that bind to one or more extracellular domains of the human olfactory receptor 10H1 (OR10H1) or variants thereof, including antigen binding proteins which can modulate the expression, function, activity and/or stability of such receptor, as well as providing nucleic acids encoding such antigen binding proteins or components thereof. Methods for detecting OR10H1 or variants thereof in a sample, including diagnostic methods, using such antigen binding proteins are also provided. Uses of such antigen binding proteins, and nucleic acids encoding the same, in medicine are further provided.

Abstract: The present invention pertains to novel modulators of resistance against T-cell mediated cytotoxic immune responses. The invention provides antagonists of immune escape mechanisms and therefore offers a novel approach for treating, or aiding a treatment, of various proliferative diseases such as cancerous diseases, in particular melanoma, pancreatic cancer and colorectal cancer. The invention specifically discloses the receptor Olfactory Receptor, Family 10, Subfamily H, Member 1 (OR10H1)as a checkpoint molecule in tumor resistance against cytotoxic T-cells. Provided is the inhibition of OR10H1 expression and/or function as a strategy for enhancing tumor susceptibility to a patients T-cell mediated immune response. Provided are antigen binding constructs for the detection of the OR10H1 protein, as well as inhibitory compounds, such as siRNA/shRNA molecules targeting OR10H1 and anti-OR10H1 antibodies, forimpairing the immune escape mediated by OR10H1.

Abstract: The present invention pertains to novel modulators of tumor resistance against T-cell mediated cytotoxic immune responses. The invention provides antagonists of tumor immune escape mechanisms and methods and other aspects related thereto, and therefore provides novel approaches for treating or aiding a treatment of various cancerous diseases and/or the diagnosis thereof. The invention specifically discloses C—C chemokine receptor type 9 (CCR9) as a checkpoint molecule in tumor resistance against cytotoxic T-cells. Provided is the inhibition of CCR9 expression, CCR9 signalling and/or CCR9-T-Cell interaction and inhibitors or antagonists thereof. In particular aspects, the invention provides combination therapeutics and/or therapies involving such inhibitors or antagonists.