Department of Pre-Clinical Therapeutics, Seattle Genetics, Inc., Bothell, WA, USA.
MAbs. 2009 Sep-Oct;1(5):481-90. doi: 10.4161/mabs.1.5.9288. Epub 2009 Sep 15.
Despite therapeutic advances, the long-term survival rates for acute myeloid leukemia (AML) are estimated to be 10% or less, pointing to the need for better treatment options. AML cells express the myeloid marker CD33, making it amenable to CD33-targeted therapy. Thus, the in vitro and in vivo anti-tumor activities of lintuzumab (SGN-33), a humanized monoclonal anti-CD33 antibody undergoing clinical evaluation, were investigated. In vitro assays were used to assess the ability of lintuzumab to mediate effector functions and to decrease the production of growth factors from AML cells. SCID mice models of disseminated AML with the multi-drug resistance (MDR)-negative HL60 and the MDR(+), HEL9217 and TF1-alpha, cell lines were developed and applied to examine the in vivo antitumor activity. In vitro, lintuzumab significantly reduced the production of TNFalpha-induced pro-inflammatory cytokines and chemokines by AML cells. Lintuzumab promoted tumor cell killing through antibody-dependent cellular cytotoxicity (ADCC) and phagocytosis (ADCP) activities against MDR(-) and MDR(+) AML cell lines and primary AML patient samples. At doses from 3 to 30 mg/kg, lintuzumab significantly enhanced survival and reduced tumor burden in vivo, regardless of MDR status. Survival of the mice was dependent upon the activity of resident macrophages and neutrophils. The results suggest that lintuzumab may exert its therapeutic effects by modulating the cytokine milieu in the tumor microenvironment and through effector mediated cell killing. Given that lintuzumab induced meaningful responses in a phase 1 clinical trial, the preclinical antitumor activities defined in this study may underlie its observed therapeutic efficacy in AML patients.
尽管治疗方法有所进步，但急性髓细胞白血病 (AML) 的长期生存率估计仍为 10%或更低，这表明需要更好的治疗选择。AML 细胞表达髓样标志物 CD33，使其能够进行 CD33 靶向治疗。因此，研究了正在进行临床评估的人源化单克隆抗 CD33 抗体 lintuzumab（SGN-33）的体外和体内抗肿瘤活性。体外测定用于评估 lintuzumab 介导效应功能的能力，并减少 AML 细胞产生生长因子。开发了具有多药耐药性（MDR）阴性 HL60 和 MDR（+）、HEL9217 和 TF1-alpha 细胞系的播散性 AML 的 SCID 小鼠模型，并应用该模型来研究体内抗肿瘤活性。在体外，lintuzumab 可显著减少 AML 细胞产生 TNFalpha 诱导的促炎细胞因子和趋化因子。Lintuzumab 通过针对 MDR（-）和 MDR（+）AML 细胞系和原发性 AML 患者样本的抗体依赖性细胞毒性（ADCC）和吞噬作用（ADCP）活性促进肿瘤细胞杀伤。在 3 至 30 mg/kg 的剂量下，无论 MDR 状态如何，lintuzumab 均可显著提高生存率并减少体内肿瘤负担。小鼠的存活取决于驻留巨噬细胞和嗜中性粒细胞的活性。结果表明，Lintuzumab 可能通过调节肿瘤微环境中的细胞因子环境并通过效应子介导的细胞杀伤来发挥其治疗作用。鉴于 lintuzumab 在 1 期临床试验中引起了有意义的反应，本研究中定义的临床前抗肿瘤活性可能是其在 AML 患者中观察到的治疗效果的基础。
