Targeting CD74 in multiple myeloma with the novel, site-specific antibody-drug conjugate STRO-001.
Targeting CD74 in multiple myeloma with the novel, site-specific antibody-drug conjugate STRO-001.
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DOI：
10.18632/oncotarget.26491
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发表时间：
2018-12-28
期刊：
影响因子：
--
通讯作者：
Molina, Arturo
中科院分区：
文献类型：
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作者：
Abrahams, Cristina L;Li, Xiaofan;Molina, Arturo
STRO-001是一种位点特异性的、主要是单一物种的、完全人的、无糖基化的抗CD 74抗体-药物缀合物，其并入了不可切割的接头-美登木素生物碱弹头，药物-抗体比率为2，其通过新型无细胞抗体合成平台产生。我们检查了STRO-001在多发性骨髓瘤（MM）中的潜在药效学和抗肿瘤作用。在MM细胞系和原发性骨髓（BM）MM活检中评估CD 74表达。在来自100%（892/892）新诊断的MM患者的CD 138+富集的浆细胞中可检测到CD 74 mRNA。免疫组织化学证实了来自新诊断的和复发/难治性MM患者的35/36个BM活检组织中的CD 74表达。细胞毒性试验证明了纳摩尔STRO-001在4/6个MM细胞系中的效力。在阿普-1和MM. 1 S荷瘤小鼠中，重复STRO-001给药提供了显著的抗肿瘤活性，根除了恶性hCD 138 + BM浆细胞并延长了存活期。在表达胰蛋白酶的MM. 1 S异种移植模型中，使用生物发光成像和BM肿瘤负荷定量证实了剂量依赖性STRO-001疗效。与预期的药效学作用一致，STRO-001在食蟹猴中诱导剂量响应性、可逆的B细胞和单核细胞消耗，高达最大耐受剂量10 mg/kg，没有脱靶毒性的证据。总的来说，这些数据表明，STRO-001是一种有前途的治疗MM的治疗剂。
STRO-001 is a site-specific, predominantly single-species, fully human, aglycosylated anti-CD74 antibody-drug conjugate incorporating a non-cleavable linker-maytansinoid warhead with a drug-antibody ratio of 2 which was produced by a novel cell-free antibody synthesis platform. We examined the potential pharmacodynamics and anti-tumor effects of STRO-001 in multiple myeloma (MM). CD74 expression was assessed in MM cell lines and primary bone marrow (BM) MM biopsies. CD74 mRNA was detectable in CD138+ enriched plasma cells from 100% (892/892) of patients with newly diagnosed MM. Immunohistochemistry confirmed CD74 expression in 35/36 BM biopsies from patients with newly diagnosed and relapsed/refractory MM. Cytotoxicity assays demonstrated nanomolar STRO-001 potency in 4/6 MM cell lines. In ARP-1 and MM.1S tumor-bearing mice, repeat STRO-001 dosing provided significant antitumor activity with eradication of malignant hCD138+ BM plasma cells and prolonged survival. In a luciferase-expressing MM.1S xenograft model, dose-dependent STRO-001 efficacy was confirmed using bioluminescent imaging and BM tumor burden quantification. Consistent with the intended pharmacodynamic effect, STRO-001 induced dose-responsive, reversible B-cell and monocyte depletion in cynomolgus monkeys, up to a maximum tolerated 10 mg/kg, with no evidence of off-target toxicity. Collectively, these data suggest that STRO-001 is a promising therapeutic agent for the treatment of MM.