Katsunari Taguchi

α1-Adrenoceptor Subtypes in the Human Carondiovascular and Urogenital Systems

Publisher Summary α 1 -adrenoceptors are most important in the human cardiovascular system in the vasulature. The subtype(s) mediating vasoconstriction in humans have not yet been firmly identified, but the radioreceptor assay appears to be a promising approach. Three subtypes of α 1 -adrenoceptors have been defined in pharmacological and molecular terms and are designated α 1A , α 1B , and α 1D . However, some data are not fully explained by these classifications, indicating the possible existence of additional subtypes. In particular, the low apparent affinity of prazosin in some functional assays has led to the proposal of an α 1 -adrenoceptor subtype with low prazosin affinity, which has been designated α 1 . This article focuses on radioligand binding and functional data of the three α 1 -adrenoceptor subtypes. α 1 -Adrenoceptors mediate numerous effects in the cardiovascular and urogenital systems. In the human lower urinary tract, α 1 -adrenoceptors mediate smooth-muscle contraction of bladder neck, urethra, and prostate. In the human prostate, the α 1A -adrenoceptor dominates at the protein level and probably is also most important for contraction. Low apparent affinities of some antagonists in functional tests with human prostate do not necessarily contradict the α 1A -adrenoceptor hypothesis but may relate to assay conditions.

Thrombopoietic activity of recombinant human interleukin-11 in nonhuman primates with ACNU-induced thrombocytopenia.

The effect of recombinant human interleukin-11 (rHuIL-11) on myelosuppressive nimustine (ACNU)-induced thrombocytopenia was assessed in nonhuman primates. A single intravenous (i.v.) injection of ACNU (15 mg/kg) was administered to cynomolgus monkeys on day 0. rHuIL-11 (100 microg/kg/day) or the vehicle was given subcutaneously (s.c.) from day 1 to day 21. In monkeys receiving ACNU, the circulating platelet count decreased to a low of 42 +/- 6 x 10(9)/L by day 21 but returned to pretreatment levels (375 +/- 48 x 10(9)/L) on day 30. Administration of rHuIL-11 prevented severe thrombocytopenia; the platelet count fell only to 138 +/- 23 x 10(9)/L on day 18, and platelet recovery was faster (458 +/- 91 x 10(9)/L by day 27) compared with that of the control animals. The size of bone marrow megakaryocytes from rHuIL-11-treated animals was larger than that of the controls, indicating that rHuIL-11 stimulated megakaryopoiesis in a myelosuppressive condition. Treatment with ACNU also caused leukopenia and moderate anemia. rHuIL-11 transiently and slightly decreased the white blood cell (WBC) and red blood cell (RBC) counts. Conversely, rHuIL-11 accelerated recovery of RBC count in the late administration period. These results support the assertion that rHuIL-11 may be an important therapeutic agent for reducing the severity and duration of thrombocytopenia following cancer chemotherapy.

Generation and characterization of a potent fully human monoclonal antibody against the interleukin-23 receptor

ABSTRACT Interleukin (IL)‐12 and IL‐23 share a common subunit (p40) and function in T‐helper (Th) 1 and Th17 immunity, respectively. Anti‐IL‐12/23p40 and specific anti‐IL‐23 antibodies are currently in clinical use for psoriasis and undergoing trials for autoimmune diseases. Since expression levels of the IL‐23 receptor are likely to be much lower than those of IL‐23, an anti‐IL‐23 receptor antibody might offer greater promise in inhibiting the IL‐23‐IL‐17 pathways involved in inflammatory disorders. To our knowledge, no anti‐IL‐23 receptor antibody has been trialed in clinical studies to date. This study describes the generation and characterization of AS2762900–00, a fully human monoclonal antibody against the IL‐23 receptor. AS2762900–00 bound both human and cynomolgus monkey IL‐23 receptors. AS2762900–00 showed potent inhibitory effects on IL‐23‐induced Kit‐225 cell proliferation compared to the existing anti‐IL‐12/23p40 antibody, ustekinumab. In a single dose administration pharmacodynamics study in cynomolgus monkeys, 1mg/kg of AS2762900–00 significantly inhibited (> 85%) IL‐23‐induced STAT3 phosphorylation in blood for up to 84 days. Therefore, AS2762900–00 represents a potent novel IL‐23‐IL‐17 pathway inhibitor with the potential to be developed into a new therapy for the treatment of autoimmune diseases.

Anti-IL-23 receptor monoclonal antibody prevents CD4+ T cell-mediated colitis in association with decreased systemic Th1 and Th17 responses

&NA; Experimental colitis studies, including T cell‐mediated colitis, indicate that IL‐23 rather than IL‐12 orchestrates intestinal inflammation in inflammatory bowel disease (IBD). Previous studies have identified the roles of IL‐12 and IL‐23 using mice deficient for their specific subunits, p35 and p19, respectively. However, these studies do not completely reflect the difference in roles between IL‐12 and IL‐23, especially since the discovery of novel IL‐12 family cytokines, which also include p35 or p19 subunits. Here, to clarify the contribution of IL‐12 and IL‐23 in T cell‐mediated colitis, we compared the efficacy of a monoclonal antibody (mAb) to an IL‐23‐specific receptor subunit with that of an anti‐IL‐12/23p40 mAb in a naive CD4+ T cell transfer model of experimental colitis, which is associated with enhanced Th1 and Th17 responses. Both antibodies almost completely prevented the development of colitis and showed reduced associated histological changes, including mucosal hyperplasia, infiltration of inflammatory cells and loss of goblet cells. The anti‐IL‐23 receptor mAb inhibited not only the systemic Th17‐response but also the Th1‐response, both of which were up‐regulated in this model. These results suggest that IL‐23, but not IL‐12, signaling is critical for the development of colitis. Blockade of IL‐23 signaling is a promising therapeutic approach for IBD.