A Phase 1, Open-Label, Randomized, Three-Period, Crossover Study to Evaluate the Relative Bioavailability of Naldemedine Granule to Tablet and the Effect of Food on the Pharmacokinetics of Naldemedine in Healthy Adult Subjects
Trispecific killer engager 161519 enhances natural killer cell function and provides anti-tumor activity against CD19-positive cancers.
2区 · 医学
作者: Ying Cheng ; Xiaodong Zheng ; Xuefu Wang ; Yongyan Chen ; Haiming Wei ; Rui Sun ; Zhigang Tian ; Haoyu Sun
Natural killer (NK) cells have gained considerable attention due to their potential in treating "cold tumors," and are therefore considered as one of the new strategies for curing cancer, by using worldwide development of their new possibilities and interventions with NK cell-related therapeutic products.
We constructed a trispecific killer engager (TriKE) consisting of anti-CD16, IL-15, and anti-CD19. This TriKE was designed to attract CD19+ tumor cells to CD16+ NK cells, whereas IL-15 sustained the proliferation, development, and survival of NK cells.
Treatment with 161519 TriKE in the presence of CD19+ targets upregulated expression of CD69, CD107a, TRAIL, IFN-γ, and TNF-α in NK cells, and significantly improved the proliferation and cytotoxicity of NK cells. NK cells "armed" with 161519 TriKE showed stronger cytolysis against CD19+ targets compared with that of "unarmed" NK cells. A preclinical model of B-cell lymphoma in human peripheral blood mononuclear cell-reconstituted xenograft mice showed significant inhibition of tumor growth and prolonged overall survival after treatment with 161519 TriKE, when compared with that in control mice or mice treated with 1619 BiKE. Combined use of IL-2 was a more effective treatment with 1619 BiKE, when compared with that using 161519 TriKE.
The newly generated 161519 TriKE enhanced the proliferation, activation, cytokine secretion, and cytotoxicity of NK cells in the presence of CD19+ tumor cells. The 161519 TriKE aided inhibition of tumor growth and prolonged the overall survival of murine xenografts, and could be used to treat CD19-positive cancers.
2018-06-26·Blood advances2区 · 医学
161533 TriKE stimulates NK-cell function to overcome myeloid-derived suppressor cells in MDS.
2区 · 医学
作者: Dhifaf Sarhan ; Ludwig Brandt ; Martin Felices ; Karolin Guldevall ; Todd Lenvik ; Peter Hinderlie ; Julie Curtsinger ; Erica Warlick ; Stephen R Spellman ; Bruce R Blazar ; Daniel J Weisdorf ; Sarah Cooley ; Daniel A Vallera ; Björn Önfelt ; Jeffrey S Miller
Myelodysplastic syndrome (MDS) is a clonal heterogeneous stem cell disorder driven by multiple genetic and epigenetic alterations resulting in ineffective hematopoiesis. MDS has a high frequency of immune suppressors, including myeloid-derived suppressor cells (MDSCs), that collectively result in a poor immune response. MDSCs in MDS patients express CD155 that ligates the T-cell immunoreceptor with immunoglobulin and ITIM domain (TIGIT) and delivers an inhibitory signal to natural killer (NK) cells. To mediate a productive immune response against MDS, negative regulatory checkpoints, like TIGIT, expressed on MDS NK cells must be overcome. NK cells can be directed to lyse MDS cells by bispecific killer engagers (BiKEs) that ligate CD16 on NK cells and CD33 on MDS cells. However, such CD16 × CD33 (1633) BiKEs do not induce the proliferative response in MDS NK cells needed to sustain their function. Here, we show that the addition of an NK stimulatory cytokine, interleukin-15 (IL-15), into the BiKE platform leads to productive IL-15 signaling without TIGIT upregulation on NK cells from MDS patients. Lower TIGIT expression allowed NK cells to resist MDSC inhibition. When compared with 1633 BiKE, 161533 trispecific killer engager (TriKE)-treated NK cells demonstrated superior killing kinetics associated with increased STAT5 phosphorylation. Furthermore, 161533 TriKE-treated MDS NK cells had higher proliferation and enhanced NK-cell function than 1633 BiKE-treated cells without the IL-15 linker. Collectively, our data demonstrate novel characteristics of the 161533 TriKE that support its application as an immunotherapeutic agent for MDS patients.
2005-12-01·Zhonghua shi yan he lin chuang bing du xue za zhi = Zhonghua shiyan he linchuang bingduxue zazhi = Chinese journal of experimental and clinical virology
[Study on treatment effectiveness and safety in children with chronic hepatitis B or C using bicyclo tablets].
作者: Hong-fei Zhang ; Xiao-jin Yang ; Shi-shu Zhu ; Zhi-qiang Xu ; Yi Dong ; Da-wei Chen ; Wen-zheng Jia ; Yu Gan ; Li-min Wang ; Hong-mei Tang
To evaluate treatment effectiveness and safety of bicyclo tablets in children with chronic hepatitis B or C.
A randomized controlled trial was conducted in 148 children with chronic hepatitis B or C for evaluating safety, tolerability, and efficacy of treatment with bicyclo tablets or Hugan tablets. Children in therapy group were treated with bicyclo tablets and control group treated with Hugan tablets.
(1) ALT and AST level decreased more prominently in therapy group than in control group (P<0.01). (2) Bicyclo was more effective than Hugan tablets (P<0.01). (3) Symptoms were ameliorated more prominently in bicyclo group than in control group (P<0.01). (4) Both groups had no significant adverse events.
Satisfactory therapeutic effect and safety were obtained with bicyclo tablets in children with chronic hepatitis B or C.