Inhibition of CRAC with a human anti-ORAI1 monoclonal antibody inhibits T-cell-derived cytokine production but fails to inhibit a T-cell-dependent antibody response in the cynomolgus monkey

Abstract

(2015) Inhibition of CRAC with a human anti-ORAI1 monoclonal antibody inhibits T-cell-derived cytokine production but fails to inhibit a T-cell-dependent antibody response in the cynomolgus monkey, Journal of Immunotoxicology, 12:2,[164][165][166][167][168][169][170][171][172][173] RESEARCH ARTICLEInhibition of CRAC with a human anti-ORAI1 monoclonal antibody inhibits T-cell-derived cytokine production but fails to inhibit a T-cell-dependent antibody response in the cynomolgus monkey 2+ entry induces proliferation and cytokine production through activation of calcineurin and the nuclear factor of activated T-cells (NFAT) transcription factor along with subsequent cytokine-related genes. It was hypothesized that the in vivo inhibition of T-cell function by blocking ORAI1 or calcineurin would lead to similar functional consequences. To test this hypothesis the activity of 2C1.1, a fully human anti-ORAI1 monoclonal antibody, and cyclosporin A (CsA) were tested in vivo for their suppressive effect on T-cell-derived cytokine production and a T-cell-dependent antibody response (TDAR) using sheep red blood cells (SRBC) in cynomolgus monkeys. Despite showing similar inhibition of ex vivo interleukin (IL)-2 production by stimulated T-cells, both molecules exhibited different pharmacologic effects on the SRBC antibody response. CsA blocked the development of SRBC-specific antibodies, while 2C1.1 failed to inhibit the antigen-specific antibody response. These surprising observations suggest that full inhibition of the CRAC channel is required to inhibit a functional immune response, consistent with findings from human patients with loss of function mutations in ORAI1.

Store-Operated Calcium Channels

“…It is worth noting, however, that attempts to translate the therapeutic potential of these mAbs in vivo have not yet succeeded. In vivo tests in cynomologus monkeys injected with the 2C1.1 mAb revealed unexpected generation of antigen-specific antibodies, despite robust inhibition of T-cell cytokine production (IL-2) ex vivo (114). This result was interpreted to indicate that full inhibition of the CRAC channel is required to suppress the antibody response, rather than the partial suppression achieved by the administration of anti-CRAC channel mAbs.…”

Ion Channels in Innate and Adaptive Immunity

“…Two independently developed monoclonal antibodies selectively bound ORAI1 (but not ORAI2 and ORAI3), inhibited CRAC currents and SOCE in lymphocytes and suppressed the proliferation and cytokine production of human PBMCs and synovial fluid cells from rheumatoid arthritis patients in vitro (358, 359). In vivo treatment with anti-ORAI1 antibodies ameliorated the severity of xenogeneic T cell–mediated GvHD in mice (358) and reduced the production of IL-2, IL-4, and IL-17 by ex vivo–stimulated T cells isolated from cynomolgus monkeys (360). Collectively, these data suggest that CRAC channel inhibition may be useful for the treatment of autoimmune diseases, transplant rejection, and allergic diseases.…”

“…Whereas proinflammatory cytokine production was impaired in T cells from Orai1 − / − , Orai1 R93W , Stim1 fl/fl CD4-Cre , or Stim2 fl/fl Cd4-Cre mice with various degrees of CRAC channel dysfunction (126, 127, 164, 168, 169), memory CD8 + T cell responses and antibody production were only impaired in Stim1 fl/fl Stim2 fl/fl Cd4-Cre mice whose T cells lack CRAC channel function completely (183). Similarly, inhibitory ORAI1 antibodies partially reduced SOCE and cytokine secretion by T cells but did not impair T-dependent antibody production (360). Patients homozygous for mutations in ORAI1 or STIM1 that lack SOCE completely, but not their heterozygous relatives with partial impairment of SOCE, show increased susceptibility to viral and bacterial infections (26, 123).…”

Anti‐ORAI1 antibody DS‐2741a, a specific CRAC channel blocker, shows ideal therapeutic profiles for allergic disease via suppression of aberrant T‐cell and mast cell activation

“…The study conducted on monkeys aimed to compare its efficacy with that of FK-506; however, it focused solely on safety evaluation and was not a disease model in particular. 27 Hence, specific indications could not be discussed.…”