The Preclinical Profile of the Duocarmycin-Based HER2-Targeting ADC SYD985 Predicts for Clinical Benefit in Low HER2-Expressing Breast Cancers
The Preclinical Profile of the Duocarmycin-Based HER2-Targeting ADC SYD985 Predicts for Clinical Benefit in Low HER2-Expressing Breast Cancers
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DOI：
10.1158/1535-7163.mct-14-0881-t
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发表时间：
2015-03-01
影响因子：
5.7
通讯作者：
Dokter, Wim H. A.
中科院分区：
文献类型：
--
作者：
van der Lee, Miranda M. C.;Groothuis, Patrick G.;Dokter, Wim H. A.
SYD 985是一种基于曲妥珠单抗和vc-seco-杜巴（一种可裂解的接头-倍癌霉素有效载荷）的HER 2靶向抗体-药物偶联物（ADC）。为了评估这种新ADC的治疗潜力，进行了体外机制研究和体内患者来源的异种移植物（PDX）研究，以比较SYD 985与T-DM 1（Kadcyla）（另一种基于曲妥珠单抗的ADC）的头对头。SYD 985和T-DM 1对HER 2具有相似的结合亲和力，并显示出相似的内化。体外细胞毒性试验显示，在HER 2 3+细胞系中具有相似的效力和功效，但在低HER 2表达的细胞系中，SYD 985的效力是T-DM 1的3- 50倍。与T-DM 1相比，SYD 985在与HER 2 3+、2+或1+细胞系混合的HER 2阴性（HER 2 0）细胞中有效地诱导了体外旁观者杀伤。在与肿瘤相关的pH条件下，组织蛋白酶-B裂解研究显示SYD 985而不是T-DM 1有效释放活性毒素。这些体外数据表明，SYD 985可能是体内HER 2表达肿瘤中更有效的ADC，特别是在低HER 2表达和/或异质性肿瘤中。与此一致，在乳腺癌PDX模型中的体内抗肿瘤研究表明，SYD 985在HER 2 3+、2+和1+模型中非常有活性，而T-DM 1仅在HER 2 3+乳腺癌PDX模型中显示出显著的抗肿瘤活性。SYD 985的这些特性可能使目标人群扩展到低HER 2表达乳腺癌患者，这是一个仍有未满足的高医疗需求的患者人群。(C)2015年AACR。
SYD985 is a HER2-targeting antibody-drug conjugate (ADC) based on trastuzumab and vc-seco-DUBA, a cleavable linker-duocarmycin payload. To evaluate the therapeutic potential of this new ADC, mechanistic in vitro studies and in vivo patient-derived xenograft (PDX) studies were conducted to compare SYD985 head-to-head with T-DM1 (Kadcyla), another trastuzumab-based ADC. SYD985 and T-DM1 had similar binding affinities to HER2 and showed similar internalization. In vitro cytotoxicity assays showed similar potencies and efficacies in HER2 3+ cell lines, but in cell lines with low HER2 expression, SYD985 was 3- to 50-fold more potent than T-DM1. In contrast with T-DM1, SYD985 efficiently induced bystander killing in vitro in HER2-negative (HER2 0) cellsmixed with HER2 3+, 2+, or 1+ cell lines. At pH conditions relevant for tumors, cathepsin-B cleavage studies showed efficient release of the active toxin by SYD985 but not by T-DM1. These in vitro data suggest that SYD985 might be a more potent ADC in HER2-expressing tumors in vivo, especially in low HER2-expressing and/or in heterogeneous tumors. In line with this, in vivo antitumor studies in breast cancer PDX models showed that SYD985 is very active in HER2 3+, 2+, and 1+ models, whereas T-DM1 only showed significant antitumor activity in HER2 3+breast cancer PDX models. These properties of SYD985 may enable expansion of the target population to patients who have low HER2-expressing breast cancer, a patient population with still unmet high medical need. (C) 2015 AACR.