HDAC Inhibitors as Epigenetic Regulators

At concentrations above 20 g/mL, TNT009 profoundly inhibited HLA antibody-triggered C3d deposition (median C3d MFI, 400 [IQR, 193-803] vs 3070 [IQR, 2442-3899] at concentrations below 20 g/mL). inhibited when TNT009 concentrations exceeded 20 g/mL. Infusions were well tolerated without serious or severe adverse events. Conclusions Treatment with TNT009 was safe and potently inhibited CP activity. Future studies in patients are required to assess the potential of TNT009 for preventing or treating antibody-mediated rejection. In a double-blind, randomized, placebo-controlled phase 1 trial in adult healthy volunteers, the authors report that TNT009, an anti-C1s monoclonal antibody, significantly inhibits complement classical pathway activation with an excellent tolerance. Antibody-mediated rejection (AMR) is increasingly recognized as one of the cardinal causes of organ allograft dysfunction and loss.1,2 Even though donor-specific antibody (DSA) binding to the transplant endothelium may cause injury via direct signaling or Fc receptor-dependent mechanisms,3,4 there are several lines of evidence suggesting that antibody-triggered complement activation by the classical pathway (CP) contributes to graft damage.5,6 While clear-cut diagnostic criteria for AMR have been well defined,7 the clinical management of Rabbit polyclonal to ANXA13 graft rejection has remained a major therapeutic challenge. There is still a need for new therapeutic paradigms to improve currently available treatment strategies. Indeed, even intense multimodal regimens have failed to completely prevent irreversible graft damage, as shown for kidney transplantation across HLA antibody barriers.8-10 One promising option may be the use of agents that specifically interfere with complement.11,12 Recent observational studies and case reports suggested that eculizumab, a monoclonal antibody against terminal component C5, may have efficacy in the prevention and treatment of acute AMR,13-16 but another PF-915275 study showed that complement inhibition was ineffective at preventing chronic AMR in patients with persistently elevated DSA, possibly due to upstream complement activation driving inflammation and subsequent tissue injury.15 An interesting alternative may be the use of agents that specifically target the CP at the level of complement component C1.12 A potential advantage of this strategy over C5 inhibition is that in addition to PF-915275 preventing terminal pathway activation, inhibition at the level of C1 prevents the production of the potent C3a anaphylatoxin and C3b/iC3b opsonins. Recent intervention studies have provided the first evidence that C1 inhibition using a C1-esterase inhibitor (C1-INH) may have some therapeutic potential in transplant settings.17-19 However, C1-INH inhibits both lectin and CPs, and is also involved in other enzymatic pathways including the plasma kallikrein-kinin (contact) system. Another more selective approach may be the use of monoclonal PF-915275 antibodies that specifically target the C1 complex. Very recently, experimental studies have shown that TNT003, a mouse monoclonal antibody against the CP-specific serine protease C1s, effectively prevented cold agglutinin-mediated deposition of complement opsonins, release of anaphylatoxins, and hemolysis in vitro.20 The same antibody potently inhibited HLA antibody-triggered complement split product deposition on HLA antigen-coated microbeads.21 These data suggested a therapeutic potential of C1s blockade in CP-driven complement-mediated disorders. Here we report on the results of a first-in-human, double-blind, randomized, placebo-controlled phase 1 trial PF-915275 designed to assess the tolerability/safety (primary endpoint) and activity of the humanized anti-C1s monoclonal antibody TNT009 in healthy volunteers.22 TNT009-containing serum samples from healthy subjects dosed with the molecule were found to inhibit ex vivo HLA antibody-triggered CP activation. These data provide the basis for systematic studies evaluating the efficacy of TNT009 in transplant settings. MATERIALS AND METHODS Study design and Objectives This first-in-human phase I trial was conducted as a single center, randomized, double-blind, placebo-controlled trial to evaluate the safety/tolerability profile and complement inhibitory potential of the humanized anti-C1s monoclonal antibody TNT009 (True North Therapeutics, Inc., South San Francisco, CA). The study was approved by the ethics committee of the Medical University Vienna and was performed in compliance with the Good Clinical Practice guidelines and the principles of the Declaration of Helsinki. The trial is.