Abrahams Cristina L, Li Xiaofan, Embry Millicent, Yu Abigail, Krimm Stellanie, Krueger Sarah, Greenland Nancy Y, Wen Kwun Wah, Jones Chris, DeAlmeida Venita, Solis Willy A, Matheny Shannon, Kline Toni, Yam Alice Y, Stafford Ryan, Wiita Arun P, Hallam Trevor, Lupher Mark, Molina Arturo
Sutro Biopharma, Inc., South San Francisco, California, USA.
MI Bioresearch, Ann Arbor, MI, USA.
Oncotarget. 2018 Dec 28;9(102):37700-37714. doi: 10.18632/oncotarget.26491.
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.
STRO-001是一种位点特异性、主要为单物种、完全人源化的去糖基化抗CD74抗体-药物偶联物，其包含一个不可裂解的连接体-美登素弹头，药物-抗体比例为2，由一种新型无细胞抗体合成平台生产。我们研究了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活检组织中评估了CD74表达。在100%（892/892）新诊断MM患者的CD138+富集浆细胞中可检测到CD74 mRNA。免疫组织化学证实，在新诊断和复发/难治性MM患者的35/36份BM活检组织中存在CD74表达。细胞毒性试验表明，STRO-001在4/6个MM细胞系中具有纳摩尔效力。在携带ARP-1和MM.1S肿瘤的小鼠中，重复给予STRO-001具有显著的抗肿瘤活性，可根除恶性hCD138+ BM浆细胞并延长生存期。在表达荧光素酶的MM.1S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STRO-001的剂量依赖性疗效。与预期的药效学作用一致，STRO-001在食蟹猴中诱导了剂量反应性、可逆性B细胞和单核细胞耗竭，最大耐受剂量为10 mg/kg，且无脱靶毒性证据。总体而言，这些数据表明STRO-001是一种有前景的MM治疗药物。
