Initial testing (stage 1) of a monoclonal antibody (SCH 717454) against the IGF-1 receptor by the Pediatric Preclinical Testing Program
Initial testing (stage 1) of a monoclonal antibody (SCH 717454) against the IGF-1 receptor by the Pediatric Preclinical Testing Program
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DOI：
10.1002/pbc.21450
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发表时间：
2008-06-01
影响因子：
3.2
通讯作者：
Smith, Malcolm A.
中科院分区：
文献类型：
--
作者：
Kolb, E. Anders;Gorlick, Richard;Smith, Malcolm A.
背景SCH 717454（19 D12）是一种针对胰岛素样生长因子1受体（IGF-1 R）的全人源抗体，IGF-1 R与多种恶性肿瘤的生长和转移表型有关。根据儿科临床前试验项目（PPTP）的体外和体内样本组评价SCH 717454的活性。程序.在0.01 - 100 nM浓度范围内检测SCH 717454对PPTP的体外抑制作用，并在0.5 mg/小鼠每周两次持续4周腹腔注射给药后检测SCH 717454对PPTP的体内抑制作用。结果SCH 717454在体外组中对细胞系的生长抑制无效。在体内，SCH 717454显著延长了20/35个实体瘤异种移植模型（57%）的无事件生存期，其中1个尤文肉瘤模型（完全缓解）和2个骨肉瘤模型（维持完全缓解）出现肿瘤消退。使用至事件时间活性指标，SCH 717454对31种可评价实体瘤异种移植物具有中等（n=9）或高（ml）活性，包括横纹肌样瘤、尤文氏瘤、横纹肌肉瘤、胶质母细胞瘤、神经母细胞瘤和骨肉瘤的异种移植物。SCH 717454对急性淋巴细胞白血病组的8种异种移植物几乎没有活性。结论. SCH 717454对PPTP的体内实体瘤组表现出广泛的抗肿瘤活性。预计将进一步表征SCH 717454与其他抗癌药物联合给药的反应和活性的分子预测因子。
Background SCH 717454 (19D12) is a fully human antibody directed against the insulin-like growth factor 1 receptor (IGF-1R), which is implicated in the growth and metastatic phenotype of a broad range of malignancies. The activity of SCH 717454 was evaluated against the in vitro and in vivo panels of the Pediatric Preclinical Testing Program (PPTP). Procedures. SCH 717454 was tested against the PPTP in vitro panel at concentrations ranging from 0.01 to 100 nM and was tested against the PPTP in vivo panel at a dose of 0.5 mg per mouse administered twice weekly for 4 weeks via intraperitoneal injection. Results. SCH 717454 was ineffective at retarding growth of cell lines in the in vitro panel. in vivo, SCH 717454 significantly increased event-free survival in 20 of 35 (57%) solid tumor xenograft models with tumor regressions in one Ewing sarcoma model (complete response) and 2 osteosarcoma models (maintained complete responses). Using the time to event activity measure, SCH 717454 had intermediate (n=9) or high ml) activity against 31 evaluable solid tumor xenografts, including xenografts from the rhabdoid tumor, Ewing, rhabdomyosarcoma, glioblastoma, neuroblastoma, and osteosarcoma panels. SCH 717454 showed little activity against the 8 xenografts of the acute lymphoblastic leukemia panel. Conclusions. SCH 717454 demonstrated broad antitumor activity against the PPTP's in vivo solid tumor panels. Further characterization of the molecular predictors of response and of the activity of combinations of SCH 717454 with other anticancer agents are anticipated.