Abstract LB-295: MEDI7247, a novel pyrrolobenzodiazepine ADC targeting ASCT2 with potentin vivoactivity across a spectrum of hematological malignancies
Abstract LB-295: MEDI7247, a novel pyrrolobenzodiazepine ADC targeting ASCT2 with potentin vivoactivity across a spectrum of hematological malignancies
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摘要 LB-295：MEDI7247，一种新型吡咯并苯二氮卓类 ADC，靶向 ASCT2，在多种血液恶性肿瘤中具有有效的体内活性
作者：
N. Monks;Kevin P. Schifferli;R. Tammali;M. Borrok;Steven R. Coats;R. Herbst;David A. Tice;N. Pore
MEDI 7247是第一种由特异性缀合至DNA交联吡咯并苯并二氮杂卓（PBD）二聚体的人抗ASCT 2单克隆抗体位点组成的ADC。ASCT 2（SLC 1A 5）是一种多通道、Na+依赖性中性氨基酸转运蛋白，介导肿瘤生长和进展所需氨基酸的摄取。ASCT 2在许多血液癌症中高度过表达，最值得注意的是多发性骨髓瘤（MM - 100%阳性）、急性髓性白血病（AML - 100%阳性）和弥漫性大B细胞淋巴瘤（DLBCL - 95%阳性）。ASCT 2在正常组织中表达较低。在3种播散性AML细胞系模型TF 1 α（ASCT 2-高）、MOLM-13（ASCT 2-低）和M.V.411（ASCT 2-高）中，与未处理对照相比，MEDI 7247（Q1 Wx 4）在检查的最低剂量水平（分别为0.05、0.1和0.1 mg/kg）下表现出显著的存活优势。进一步举例说明MEDI 7247的活性，到研究结束时，TF 1 α和MOLM-13模型均未达到50%存活率，其中TF 1 α在>200天时存活率为80%，MOLM-13在>180天时存活率为70%。类似地，在TF 1 α模型中，单剂量的MEDI 7247在0.05 mg/kg下在>200天时导致60%的存活率。还在播散性AML PDX（ASCT 2-低）模型中以0.05、0.1和0.4mg/kg测试MEDI 7247。在0.1和0.4 mg/kg剂量下观察到存活率显著改善，较高剂量水平延长存活时间>80天。通过监测外周血CD 33 +ve细胞进一步证实了MEDI 7247活性，所述细胞最初消退，其中再现的时间先于存活。多发性骨髓瘤是表现出高水平ASCT 2表达的另一个适应症。在3种播散性MM细胞系模型NCI-H929（ASCT 2-高）、MM. 1 S（ASCT 2-培养基）和OPM 2（ASCT 2-培养基）中检查了MEDI 7247（Q1 Wx 4）的功效，在检查的最低剂量水平（分别为0.1、0.1和0.05 mg/kg）下，存活率相对于对照显著改善。还在皮下DLBCL模型KARPAS 422（ASCT 2-高）中检查了MEDI 7247（Q1 Wx 4）的活性。在所有试验剂量水平（0.1、0.2、0.3和0.4 mg/kg）下均观察到肿瘤消退，较高的两个剂量水平导致肿瘤完全消退，150天后无再生长。此外，MEDI 7247（Q1 Wx 4）对播散性697（ASCT 2-低）（急性淋巴细胞白血病- ALL）和RAJI（ASCT 2-高）（伯基特淋巴瘤）模型有效。在最低剂量0.05 mg/kg下，在两种肿瘤模型中均观察到显著的生存优势。总之，MEDI 7247在所有测试的肿瘤适应症和不同水平的ASCT 2表达中表现出抗肿瘤功效。这些数据支持MEDI 7247在ASCT 2阳性血液恶性肿瘤中的使用。MEDI 7247目前处于1期临床试验阶段。引文格式：诺埃尔R.放大图片作者：Kevin P.放大图片作者：Jack Borrok.放大图片作者：罗纳德赫布斯特，大卫A. Tice，Nabendu Pore. MEDI 7247，一种靶向ASCT 2的新型吡咯并苯并二氮杂卓类ADC，在血液恶性肿瘤谱中具有强效体内活性[摘要]。在：2018年美国癌症研究协会年会论文集; 2018年4月14日至18日;芝加哥，IL。Philadelphia（PA）：AACR; Cancer Res 2018;78（13 Suppl）：Abstract nr LB-295.
MEDI7247 is a first in class ADC consisting of a human anti-ASCT2 monoclonal antibody site specifically conjugated to DNA cross-linking pyrrolobenzodiazepine (PBD) dimers. ASCT2 (SLC1A5) is a multi-pass, Na+-dependent neutral amino acid transporter that mediates the uptake of amino acids required for tumor growth and progression. ASCT2 is highly overexpressed in many hematologic cancers, most notably Multiple Myeloma (MM - 100% positive), Acute Myeloid Leukemia (AML - 100% positive) and Diffuse Large B cell lymphoma (DLBCL - 95% positive). ASCT2 expression is low in normal tissues. MEDI7247 (Q1Wx4) demonstrated a significant survival advantage in 3 disseminated AML cell line models, TF1α(ASCT2-High), MOLM-13(ASCT2-low) and M.V.411(ASCT2-High), when compared to the untreated control at the lowest dose levels examined: 0.05, 0.1 and 0.1 mg/kg, respectively. Further exemplifying the activity of MEDI7247, both the TF1α and MOLM-13 models did not reach 50% survival by the end of the study, with 80% survival at >200 days for TF1α and 70% survival at >180 days for MOLM-13. Similarly, a single dose of MEDI7247 in the TF1α model resulted in a 60% survival at >200 days at 0.05 mg/kg. MEDI7247 was also tested in a disseminated AML PDX(ASCT2-low) model at 0.05, 0.1 and 0.4 mg/kg. A significant improvement in survival was observed at both 0.1 and 0.4 mg/kg with the higher dose level extending survival by >80 days. MEDI7247 activity was further confirmed by monitoring peripheral blood CD33+ve cells, which initially receded, with the timing of reappearance preempting survival. Multiple Myeloma is another indication that exhibits a high level of ASCT2 expression. MEDI7247 (Q1Wx4) efficacy was examined in 3 disseminated MM cell line models, NCI-H929(ASCT2-High), MM.1S(ASCT2-medium) and OPM2(ASCT2-Medium), with a significant improvement in survival from control at the lowest dose levels examined: 0.1, 0.1 and 0.05 mg/kg, respectively. The activity of MEDI7247 (Q1Wx4) was also examined in the subcutaneous DLBCL model KARPAS 422(ASCT2-High). Tumor regressions were observed at all dose levels tested (0.1, 0.2, 0.3 and 0.4 mg/kg), with the higher two dose levels resulting in complete tumor regression without regrowth beyond 150 days. Additionally, MEDI7247 (Q1Wx4) is efficacious against the disseminated 697(ASCT2-Low) (Acute Lymphoblastic Leukemia - ALL) and RAJI(ASCT2-High) (Burkitt9s lymphoma) models. A significant survival advantage was seen in both tumor models at the lowest dose examined of 0.05 mg/kg. In conclusion, MEDI7247 demonstrates antitumor efficacy across all tumor indications tested and varying levels of ASCT2 expression. These data support the use of MEDI7247 in ASCT2 positive hematological malignancies. MEDI7247 is currently in Phase 1 clinical trials. Citation Format: Noel R. Monks, Kevin P. Schifferli, Ravinder Tammali, M. Jack Borrok, Steven R. Coats, Ronald Herbst, David A. Tice, Nabendu Pore. MEDI7247, a novel pyrrolobenzodiazepine ADC targeting ASCT2 with potent in vivo activity across a spectrum of hematological malignancies [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr LB-295.