Tigatuzumab

Chronic moderate-to-severe plaque psoriasis frequently requires long-term biol. treatment, but treatment gaps resulting in relapse are not uncommon.Tildrakizumab is a high-affinity, humanized, IgG1kappa, anti-interleukin-23p19 monoclonal antibody approved to treat plaque psoriasis.This study focus on adult patients with moderate-to-severe plaque psoriasis required tildrakizumab-treated patients who achieved ≥ 75% improvement from baseline Psoriasis Area and Severity Index score (PASI 75; responders) at Week 28 to be rerandomized to either continued tildrakizumab treatment or withdrawal (placebo) with retreatment with their initial dose of tildrakizumab upon relapse.Of 116 patients continuously treated with tildrakizumab 100 mg after Week 28, 92.6%, 81.5% and 49.6% achieved PASI 50, PASI 75 and PASI 90, resp., at Week 64.From Weeks 28 - 64 of reSURFACE 1, tildrakizumab 100 mg was well tolerated and efficacious in patients receiving continuous treatment; patients withdrawn to placebo recovered response within a median of 28 days.The durability of tildrakizumab responses and rapid regain of efficacy after relapse and retreatment support long-term clin. use of tildrakizumab for the treatment of moderate-to-severe psoriasis.

Activation of death receptor-5 (DR5) leads to the formation of death-inducing signaling complex (DISC) for apoptotic signaling. TRA-8, a DR5 specific agonistic antibody, has demonstrated significant cytotoxic activity in vitro and in vivo without inducing hepatotoxicity. Calmodulin (CaM) that is overexpressed in breast cancer plays a critical role in regulating DR5-mediated apoptosis. However, the mechanism of CaM in regulating DR5-mediated apoptotic signaling remains unknown. In this study, we characterized CaM binding to DR5-mediated DISC for apoptosis in TRA-8 sensitive breast cancer cell lines using co-immunoprecipitation, fluorescence microscopic imaging, caspase signaling analysis, and cell viability assay. Results show that upon DR5 activation, CaM was recruited into DR5-mediated DISC in a calcium dependent manner. CaM antagonist, trifluoperazine (TFP), inhibited CaM recruitment into the DISC and attenuated DISC formation. DR5 oligomerization is critical for DISC formation for apoptosis. TFP decreased TRA-8 activated DR5 oligomerization, which was consistent with TFP's effect on DR5-mediated DISC formation. TFP and Ca²⁺ chelator, EGTA, impeded TRA-8-activated caspase-dependent apoptotic signaling, and TFP decreased TRA-8-induced cell cytotoxicity. These results demonstrated CaM binding to DR5-mediated DISC in a calcium dependent manner and may identify CaM as a key regulator of DR5-mediated DISC formation for apoptosis in breast cancer. J. Cell. Biochem. 118: 2285-2294, 2017. © 2017 Wiley Periodicals, Inc.