医学
抗体-药物偶联物
横纹肌肉瘤
小儿癌症
癌症研究
恶性肿瘤
神经母细胞瘤
组织微阵列
癌症
抗体
内科学
肿瘤科
肉瘤
单克隆抗体
病理
免疫学
细胞培养
生物
遗传学
作者
Nathan M. Kendsersky,Jarrett Lindsay,E. Anders Kolb,Malcolm A. Smith,Beverly A. Teicher,Stephen W. Erickson,Eric J. Earley,Yaël P. Mossé,Daniel Martı́nez,Jennifer Pogoriler,Kateryna Krytska,Khushbu Patel,David Groff,Matthew Tsang,Samson Ghilu,Yifei Wang,Steven Seaman,Feng Yang,Brad St. Croix,Richard Görlick,Raushan T. Kurmasheva,Peter J. Houghton,John M. Maris
标识
DOI:10.1158/1078-0432.ccr-20-4221
摘要
Patients with relapsed pediatric solid malignancies have few therapeutic options, and many of these patients die of their disease. B7-H3 is an immune checkpoint protein encoded by the CD276 gene that is overexpressed in many pediatric cancers. Here, we investigate the activity of the B7-H3-targeting antibody-drug conjugate (ADC) m276-SL-PBD in pediatric solid malignancy patient-derived (PDX) and cell line-derived xenograft (CDX) models.B7-H3 expression was quantified by RNA sequencing and by IHC on pediatric PDX microarrays. We tested the safety and efficacy of m276-SL-PBD in two stages. Randomized trials of m276-SL-PBD of 0.5 mg/kg on days 1, 8, and 15 compared with vehicle were performed in PDX or CDX models of Ewing sarcoma (N = 3), rhabdomyosarcoma (N = 4), Wilms tumors (N = 2), osteosarcoma (N = 5), and neuroblastoma (N = 12). We then performed a single mouse trial in 47 PDX or CDX models using a single 0.5 m/kg dose of m276-SL-PBD.The vast majority of PDX and CDX samples studied showed intense membranous B7-H3 expression (median H-score 177, SD 52). In the randomized trials, m276-SL-PBD showed a 92.3% response rate, with 61.5% of models showing a maintained complete response (MCR). These data were confirmed in the single mouse trial with an overall response rate of 91.5% and MCR rate of 64.4%. Treatment-related mortality rate was 5.5% with late weight loss observed in a subset of models dosed once a week for 3 weeks.m276-SL-PBD has significant antitumor activity across a broad panel of pediatric solid tumor PDX models.
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