Sadun Rebecca E, Hsu Wen-En, Zhang Nan, Nien Yu-Chih, Bergfeld Scott A, Sabzevari Helen, Lutsiak M E Christine, Khawli Leslie, Hu Peisheng, Epstein Alan L
Department of Pathology, Keck School of Medicine, University of Southern California, Los Angeles, CA 90033, USA.
J Immunother. 2008 Apr;31(3):235-45. doi: 10.1097/CJI.0b013e31816a88e0.
OX40L is a member of the tumor necrosis factor superfamily that provides a costimulatory signal to CD4+ and CD8+ T cells while inhibiting the effects of suppressive CD4+ CD25+ regulatory T cells. Because of this dual activity, OX40L may provide significant antitumor immunity in tumor-bearing mice. To study its clinical potential, a fusion protein consisting of mOX40L linked to the C-terminus of the Fc fragment of immunoglobulin was genetically engineered. After demonstrating its potency in vitro, several assays were performed to evaluate its antitumor effect in comparison to the OX40 agonist antibody OX86. Dosing studies in Colon 26-bearing and renal cell carcinoma (RENCA)-bearing mice showed that although OX86 produced modest tumor regression, Fc-mOX40L produced complete remission in both tumor models. Survival studies confirmed these results and showed that Fc-mOX40L treatment produced lasting responses throughout the 5-month observation period. Flow cytometric analysis of treated and untreated tumors and tumor-draining lymph nodes identified a qualitative difference in the activity of Fc-mOX40L compared with OX86 treatment as evidenced by differences in lymphoid and macrophage populations. These studies reflect the profound therapeutic potential of Fc-mOX40L, which substantially exceeds the agonist antibody OX86 in ability to produce complete tumor remissions and promote long-term survival in solid tumor models.
OX40L是肿瘤坏死因子超家族的一员，它能为CD4+和CD8+ T细胞提供共刺激信号，同时抑制抑制性CD4+ CD25+调节性T细胞的作用。由于这种双重活性，OX40L可能在荷瘤小鼠中提供显著的抗肿瘤免疫力。为了研究其临床潜力，一种由与免疫球蛋白Fc片段C末端相连的mOX40L组成的融合蛋白被基因工程改造。在证明其体外效力后，进行了几项试验以评估其与OX40激动剂抗体OX86相比的抗肿瘤效果。在荷Colon 26和荷肾细胞癌（RENCA）小鼠中的给药研究表明，尽管OX86产生了适度的肿瘤消退，但Fc-mOX40L在两种肿瘤模型中均产生了完全缓解。生存研究证实了这些结果，并表明Fc-mOX40L治疗在整个5个月的观察期内产生了持久的反应。对治疗和未治疗的肿瘤以及肿瘤引流淋巴结的流式细胞术分析确定，与OX86治疗相比，Fc-mOX40L的活性存在质的差异，这在淋巴细胞和巨噬细胞群体的差异中得到了证明。这些研究反映了Fc-mOX40L的巨大治疗潜力，在实体瘤模型中，其产生完全肿瘤缓解和促进长期生存的能力大大超过激动剂抗体OX86。
