Initial testing of a monoclonal antibody (IMC-A12) against IGF-1R by the Pediatric Preclinical Testing Program.
Initial testing of a monoclonal antibody (IMC-A12) against IGF-1R by the Pediatric Preclinical Testing Program.
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DOI：
10.1002/pbc.22367
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发表时间：
2010-07-01
影响因子：
3.2
通讯作者：
Smith, Malcolm A.
中科院分区：
文献类型：
--
作者：
Houghton, Peter J.;Morton, Christopher L.;Gorlick, Richard;Kolb, E. Anders;Keir, Stephen T.;Reynolds, C. Patrick;Kang, Min H.;Maris, John M.;Wu, Jianrong;Smith, Malcolm A.
许多儿童恶性肿瘤，包括肉瘤、神经母细胞瘤和肾母细胞瘤，均存在活性的1型胰岛素样生长因子受体（IGF-1R）及其配体IGF-1/IGF-2的自分泌。IMC-A12是一种完全人IgG1抗体，可阻止配体与IGF-1R结合。IMC-A12在0.01 nM至0.1 μM的浓度范围内暴露96小时，对儿科临床前测试计划（PPTP）的23个细胞系进行体外评估。IMC-A12以1 mg/只腹腔注射，每周2次，连续6周进行体内试验。在体外，IMC-A12诱导的T/C值小于50%的只有3种细胞系，横纹肌肉瘤细胞系（Rh41）和尤文氏肉瘤细胞系（TC-71和CHLA-9）。在体内，在34例可评估的实体瘤异种移植物中，IMC-A12诱导的EFS分布与对照组相比有显著差异（71%）。使用PPTP“事件发生时间”活性测量，IMC-A12在33例异种移植物中诱导了中等（n=13）或高（n=1）活性，可用于该活性测量，包括6例横纹肌肉瘤移植中的6例，5例骨肉瘤移植中的3例，5例神经母细胞瘤移植中的2例，5例尤文氏肉瘤移植中的1例。唯一观察到的客观反应是在异种横纹肌肉瘤移植（Rh28）中观察到的，该移植获得了维持的完全反应。IMC-A12对PPTP体内实体瘤显示出广泛的抗肿瘤活性，其活性主要是抑制肿瘤生长而不是肿瘤消退。IMC-A12在体内对PPTP的异种横纹肌肉瘤表现出最大的活性。
Many childhood malignancies including sarcomas, neuroblastoma and Wilms tumor show the presence of both, active, type-1-insulin-like growth factor receptor (IGF-1R), and the autocrine production of its ligands IGF-1/IGF-2. IMC-A12 is a fully human IgG1 antibody that prevents ligand binding to the IGF-1R. IMC-A12 was evaluated against the 23 cell lines of the Pediatric Preclinical Testing Program (PPTP) in vitro panel using 96 hour exposure at concentrations ranging from 0.01 nM to 0.1 μM. IMC-A12 was tested in vivo at a dose of 1 mg/mouse administered intraperitoneally twice weekly for six weeks. In vitro, IMC-A12 induced T/C values less than 50% in only three cell lines, a rhabdomyosarcoma cell line (Rh41) and two Ewing sarcoma cell lines (TC-71 and CHLA-9). In vivo, IMC-A12 induced significant differences in EFS distribution compared to control in 24 of 34 (71%) evaluable solid tumor xenografts. Using the PPTP “time to event” activity measure, IMC-A12 induced intermediate (n=13) or high (n=1) activity in 33 xenografts evaluable for this activity measure, including 6 of 6 rhabdomyosarcoma xenografts, 3 of 5 osteosarcoma xenografts, 2 of 5 neuroblastoma xenografts, and 1 of 5 Ewing sarcoma xenografts. The only objective response observed was observed in a rhabdomyosarcoma xenograft (Rh28) that achieved a maintained complete response. IMC-A12 demonstrated broad antitumor activity against the PPTP’s in vivo solid tumor panels, with the activity primarily being tumor growth inhibition rather than tumor regression. IMC-A12 showed its greatest activity in vivo against the PPTP’s rhabdomyosarcoma xenografts.
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影响因子：
5.7
作者：
Wang, Y;Hailey, J;Pachter, JA
通讯作者：
Pachter, JA
影响因子：
3.2
作者：
Houghton, Peter J.;Morton, Christopher L.;Smith, Malcolm A.
通讯作者：
Smith, Malcolm A.
影响因子：
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作者：
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