Preclinical Characterization of AMG 330, a CD3/CD33-Bispecific T-Cell-Engaging Antibody with Potential for Treatment of Acute Myelogenous Leukemia
Preclinical Characterization of AMG 330, a CD3/CD33-Bispecific T-Cell-Engaging Antibody with Potential for Treatment of Acute Myelogenous Leukemia
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DOI：
10.1158/1535-7163.mct-13-0956
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发表时间：
2014-06-01
影响因子：
5.7
通讯作者：
Rattel, Benno
中科院分区：
文献类型：
--
作者：
Friedrich, Matthias;Henn, Anja;Rattel, Benno
急性髓性白血病（AML）患者对新型治疗方案的需求很高。一种可能的方法是双特异性T细胞接合（BiTE，Amgen的注册商标）抗体AMG 330，其对CD 3和唾液酸结合凝集素CD 33（SIGLEC-3）具有双重特异性，其经常在AML原始细胞和白血病干细胞的表面上表达。AMG 330以低纳摩尔亲和力与人和食蟹猴来源的CD 33和CD 34结合。每个细胞表达14，400至56，700个CD 33分子的11种人AML细胞系均被先前静息的AMG 330重定向T细胞强效裂解，EC 50值范围为0.4 pmol/L至3 pmol/L（18-149 pg/mL）。孵育40小时后实现完全裂解。在存在AML细胞的情况下，AMG 330特异性诱导CD 69和CD 25的表达以及IFN-γ、TNF、白细胞介素（IL）-2、IL-10和IL-6的释放。AMG 330介导食蟹猴骨髓穿刺液中CD 33阳性细胞的离体自体耗竭。AML患者骨髓中发现的浓度的可溶性CD 33对AMG 330的活性无显著影响。CD 33在新活化的T细胞上的新表达可忽略不计，因为在所测试的10个人供体中仅3个中其限于6%的T细胞。每日静脉给予低至0.002 mg/kg AMG 330可显著延长过继转移人MOLM-13 AML细胞和人T细胞的免疫缺陷小鼠的生存期。AMG 330作为AML的潜在疗法值得进一步开发。(C)2014年AACR。
There is high demand for novel therapeutic options for patients with acute myelogenous leukemia (AML). One possible approach is the bispecific T-cell-engaging (BiTE, a registered trademark of Amgen) antibody AMG 330 with dual specificity for CD3 and the sialic acid-binding lectin CD33 (SIGLEC-3), which is frequently expressed on the surface of AML blasts and leukemic stem cells. AMG 330 binds with low nanomolar affinity to CD33 and CD3 epsilon of both human and cynomolgus monkey origin. Eleven human AML cell lines expressing between 14,400 and 56,700 CD33 molecules per cell were all potently lysed with EC50 values ranging between 0.4 pmol/L and 3 pmol/L (18-149 pg/mL) by previously resting, AMG 330-redirected T cells. Complete lysis was achieved after 40 hours of incubation. In the presence of AML cells, AMG 330 specifically induced expression of CD69 and CD25 as well as release of IFN-gamma, TNF, interleukin (IL)-2, IL-10, and IL-6. Ex vivo, AMG 330 mediated autologous depletion of CD33-positive cells from cynomolgous monkey bone marrow aspirates. Soluble CD33 at concentrations found in bone marrow of patients with AML did not significantly affect activities of AMG 330. Neoexpression of CD33 on newly activated T cells was negligible as it was limited to 6% of T cells in only three out of ten human donors tested. Daily intravenous administration with as low as 0.002 mg/kg AMG 330 significantly prolonged survival of immunodeficient mice adoptively transferred with human MOLM-13 AML cells and human T cells. AMG330 warrants further development as a potential therapy for AML. (C) 2014 AACR.