Anti-TYRO3 monoclonal antibody

Background TAM receptors (Tyro3, Axl and Met) are expressed in hematopoietic tissues. The roles of the three receptors in hematopoiesis are, however, largely unknown. We investigated the role of TAM receptors in regulating erythropoiesis. Design and Methods Single and double mutant mice for Axl and Mer were used in the study. Cellularity of bone marrow and spleen, hematologic parameters, flow cytometry analysis of erythroid cell maturation, erythropoietic response to acute hemolytic anemia, bone marrow transplantation and the expression of erythropoisis were analyzed to evaluate the function of Axl and Met in erythropoiesis. Results Axl and Mer, but not Tyro3, were constitutively expressed in developing erythroid cells. Mice lacking Axl and Mer (Axl(-/-)Me(-/-)) had impaired erythropoiesis in bone marrow and expanded splenic erythropoiesis. We found an inhibition of differentiation at the transition from erythroid progenitors to proerythroblasts in Axl(-/-)Mer(-/-) mice. These mice exhibited a low rate of erythropoietic response to acute anemia induced by phenylhydrazine. Bone marrow transplantation studies showed that the impaired erythropoiesis in Axl(-/-)Mer(-/-) mice is erythroid cell-autonomous. TAM receptors may influence erythropoiesis through the regulation of GATA-1 erythropoietin receptor and EpoR expression in erythroid progenitors. Notably, mice lacking single Axl or Mer exhibited normal erythropoiesis in steady-state conditions. Conclusions Axl and Mer play an important role in regulating erythropoiesis. This finding provides a novel insight into the mechanism of erythropoiesis.

BACKGROUND: Muscle-invasive bladder cancer (MIBC) is an aggressive neoplasm with poor prognosis, lacking effective therapeutic targets. Oncogenic dependency on members of the TAM tyrosine kinase receptor family (TYRO3, AXL, MERTK) has been reported in several cancer types, but their role in bladder cancer has never been explored. METHODS: TAM receptor expression was evaluated in two series of human bladder tumours by gene expression (TCGA and CIT series), immunohistochemistry and western blotting analyses (CIT series). The role of the different TAM receptors was assessed by loss-of-function experiments and pharmaceutical inhibition in vitro and in vivo. RESULTS: We reported a significantly higher expression of TYRO3, but not AXL or MERTK, in both non-MIBCs and MIBCs, compared to normal urothelium. Loss-of-function experiments identified a TYRO3-dependency of bladder carcinoma-derived cells both in vitro and in a mouse xenograft model, whereas AXL and MERTK depletion had only a minor impact on cell viability. Accordingly, TYRO3-dependent bladder tumour cells were sensitive to pharmacological treatment with two pan-TAM inhibitors. Finally, growth inhibition upon TYRO3 depletion relies on cell cycle inhibition and apoptosis associated with induction of tumour-suppressive signals. CONCLUSIONS: Our results provide a preclinical proof of concept for TYRO3 as a potential therapeutic target in bladder cancer.