The B7-H3-Targeting Antibody-Drug Conjugate m276-SL-PBD Is Potently Effective Against Pediatric Cancer Preclinical Solid Tumor Models.
The B7-H3-Targeting Antibody-Drug Conjugate m276-SL-PBD Is Potently Effective Against Pediatric Cancer Preclinical Solid Tumor Models.
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DOI：
10.1158/1078-0432.ccr-20-4221
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发表时间：
2021-05-15
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影响因子：
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通讯作者：
Maris JM
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作者：
Kendsersky NM;Lindsay J;Kolb EA;Smith MA;Teicher BA;Erickson SW;Earley EJ;Mosse YP;Martinez D;Pogoriler J;Krytska K;Patel K;Groff D;Tsang M;Ghilu S;Wang Y;Seaman S;Feng Y;Croix BS;Gorlick R;Kurmasheva R;Houghton PJ;Maris JM
复发的儿童实体恶性肿瘤患者几乎没有治疗选择，其中许多患者死于疾病。B7-H3是一种由CD276基因编码的免疫检查点蛋白，在许多儿童癌症中过度表达。在这里，我们研究了b7 - h3靶向抗体-药物偶联物（ADC） m276-SL-PBD在儿童实体恶性肿瘤患者源性和细胞系源性异种移植物（PDX和CDX）模型中的活性。通过RNA测序和免疫组织化学在儿童PDX芯片上量化B7-H3的表达。我们分两个阶段测试了m276-SL-PBD的安全性和有效性。在Ewing肉瘤（N=3）、横纹肌肉瘤（N=4）、Wilms肿瘤（N=2）、骨肉瘤（N=5）和神经母细胞瘤（N=12）的PDX或CDX模型中，与对照剂相比，m276-SL-PBD在第1、8和15天的随机试验中为0.5mg/kg。然后，我们在47个PDX或CDX模型中使用单剂量0.5 m/kg的m276-SL-PBD进行了单小鼠试验（SMT）。绝大多数PDX和CDX样本显示强烈的膜性B7-H3表达（H-score中位数为177，SD为52）。在随机试验中，m276-SL-PBD的缓解率为92.3%，61.5%的模型显示维持完全缓解（MCR）。这些数据在单小鼠试验中得到证实，总有效率为91.5%，MCR率为64.4%。治疗相关死亡率为5.5%，在每周给药x3次的模型子集中观察到晚期体重减轻。m276-SL-PBD在广泛的儿童实体肿瘤PDX模型中具有显著的抗肿瘤活性。
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 and cell line-derived xenograft (PDX and CDX) models. B7-H3 expression was quantified by RNA sequencing and by immunohistochemistry on pediatric PDX microarrays. We tested the safety and efficacy of m276-SL-PBD in two stages. Randomized trials of m276-SL-PBD of 0.5mg/kg on days 1, 8, and 15 compared to 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 (SMT) 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 weekly x 3. m276-SL-PBD has significant anti-tumor activity across a broad panel of pediatric solid tumor PDX models.