Piao Xiuhong, Ozawa Tatsuhiko, Hamana Hiroshi, Shitaoka Kiyomi, Jin Aishun, Kishi Hiroyuki, Muraguchi Atsushi
Department of Immunology, Graduate School of Medicine and Pharmaceutical Sciences, University of Toyama , Toyama, Japan.
Department of Immunology, College of Basic Medical Sciences, Harbin Medical University , Nangang District , Harbin, China.
Oncoimmunology. 2016 May 4;5(5):e1131380. doi: 10.1080/2162402X.2015.1131380. eCollection 2016 May.
Agonistic tumor necrosis factor (TNF)-related apoptosis-inducing ligand (TRAIL)-receptor-specific antibodies are attractive antitumor therapeutics. Recently, our group has generated several human monoclonal antibodies (mAbs) to TRAIL-receptor-1 (TRAIL-R1) (TR1-IgGs) using ISAAC technology. However, these TR1-IgGs did not demonstrate ideal apoptosis-inducing capacity in the absence of additional antibodies. To overcome this limitation, we class-switched the TR1-IgGs to TRAIL-R1 IgM antibodies (TR1-IgMs); TR1-IgMs might possess high valency and facilitate the crosslinking of the cell surface receptors. We showed that the TR1-IgMs bound TRAIL-R1, activated the caspase signal, and induced strong apoptosis (100-fold higher compared with the IgG form in one case) in human tumor cell lines without any additional crosslinking in vitro. We further demonstrated that these TR1-IgMs dramatically inhibited tumor growth in a xenograft model through the caspase activation cascade. These data suggest that TR1-IgMs may become potential immunotherapeutic agents for cancer therapy.
激动性肿瘤坏死因子（TNF）相关凋亡诱导配体（TRAIL）受体特异性抗体是颇具吸引力的抗肿瘤治疗药物。最近，我们团队利用ISAAC技术制备了几种针对TRAIL受体1（TRAIL-R1）的人源单克隆抗体（mAb）（TR1-IgG）。然而，在没有额外抗体的情况下，这些TR1-IgG并未表现出理想的凋亡诱导能力。为克服这一局限，我们将TR1-IgG转换为TRAIL-R1 IgM抗体（TR1-IgM）；TR1-IgM可能具有高亲和力并促进细胞表面受体的交联。我们发现，TR1-IgM可结合TRAIL-R1，激活半胱天冬酶信号，并在体外无需任何额外交联的情况下，在人肿瘤细胞系中诱导强烈的凋亡（在一个案例中，比IgG形式高100倍）。我们进一步证明，这些TR1-IgM通过半胱天冬酶激活级联反应在异种移植模型中显著抑制肿瘤生长。这些数据表明，TR1-IgM可能成为癌症治疗的潜在免疫治疗药物。
