A.I. duPont Hospital for Children, Wilmington, Delaware.
Pediatr Blood Cancer. 2014 Oct;61(10):1816-21. doi: 10.1002/pbc.25099. Epub 2014 Jun 9.
Glembatumumab vedotin is an antibody-auristatin conjugate that targets cells expressing the transmembrane glycoprotein NMB (GPNMB, also known as osteoactivin). It has entered clinical evaluation for adult cancers that express GPNMB, including melanoma and breast cancer.
Glembatumumab vedotin was administered intravenously at a dose of 2.5 mg/kg using a weekly × 3 schedule, and its antitumor activity was evaluated against selected Pediatric Preclinical Testing Program (PPTP) solid tumor xenografts using standard PPTP response metrics.
Among PPTP xenografts, GPNMB was primarily expressed on the osteosarcoma xenografts, all of which expressed GPNMB at the RNA level, although at varying levels. Protein expression assessed by immunohistochemistry (IHC) showed variation across the osteosarcoma xenografts with one model showing no tumor cell expression. Glembatumumab vedotin induced statistically significant differences (P < 0.05) in event-free survival (EFS) distribution compared to control in each of the six osteosarcoma models studied. Three of six osteosarcoma xenografts demonstrated a maintained complete response (MCR). Two other xenografts showed progressive disease with growth delay, while the final xenograft showed progressive disease with no growth delay. Two of the osteosarcoma xenografts with MCRs showed the highest GPNMB expression at the RNA level. Conversely, the xenograft with the lowest GPNMB mRNA expression had the poorest response to glembatumumab vedotin. Two rhabdomyosarcoma xenografts that did not express GPNMB showed limited responses to glembatumumab vedotin.
Glembatumumab vedotin yielded high-level activity against three of six osteosarcoma xenografts, with evidence for response being related to GPNMB expression levels.
吉妥珠单抗奥唑米星是一种靶向表达跨膜糖蛋白 NMB（GPNMB，也称为成骨激活素）的抗体-auristatin 偶联物。它已进入针对表达 GPNMB 的成人癌症的临床评估，包括黑色素瘤和乳腺癌。
吉妥珠单抗奥唑米星以 2.5mg/kg 的剂量静脉内给药，每周 3 次，使用标准儿科临床前测试计划（PPTP）实体瘤异种移植模型评估其针对选定的 PPTP 实体瘤异种移植的抗肿瘤活性。
在 PPTP 异种移植中，GPNMB 主要在骨肉瘤异种移植中表达，所有这些异种移植均在 RNA 水平表达 GPNMB，尽管表达水平不同。免疫组织化学（IHC）评估的蛋白表达显示，在不同的骨肉瘤异种移植中存在差异，其中一个模型显示没有肿瘤细胞表达。与对照组相比，吉妥珠单抗奥唑米星在研究的六个骨肉瘤模型中的每一个中均导致无事件生存（EFS）分布的统计学显着差异（P <0.05）。在六个骨肉瘤异种移植中，有三个显示出持续完全缓解（MCR）。另外两个异种移植显示出进展性疾病伴生长延迟，而最后一个异种移植显示出进展性疾病而无生长延迟。具有 MCR 的两个骨肉瘤异种移植显示出最高的 GPNMB 在 RNA 水平上的表达。相反，GPNMB mRNA 表达最低的异种移植对吉妥珠单抗奥唑米星的反应最差。两个不表达 GPNMB 的横纹肌肉瘤异种移植对吉妥珠单抗奥唑米星的反应有限。
吉妥珠单抗奥唑米星对六个骨肉瘤异种移植中的三个产生了高水平的活性，并且对 GPNMB 表达水平的反应证据。
