Huang Jing, Agoston Agoston T, Guo Peng, Moses Marsha A
Vascular Biology Program Boston Children's Hospital Boston MA 02115 USA.
Department of Surgery Boston Children's Hospital and Harvard Medical School Boston MA 02115 USA.
Adv Sci (Weinh). 2020 Nov 3;7(24):2002852. doi: 10.1002/advs.202002852. eCollection 2020 Dec.
Outcomes for pancreatic cancer (PC) patients remain strikingly poor with a 5-year survival of less than 8% due to the lack of effective treatment modalities. Here, a novel precision medicine approach for PC treatment is developed, which is composed of a rationally designed tumor-targeting ICAM1 antibody-drug conjugate (ADC) with optimized chemical linker and cytotoxic payload, complemented with a magnetic resonance imaging (MRI)-based molecular imaging approach to noninvasively evaluate the efficiency of ICAM1 ADC therapy. It is shown that ICAM1 is differentially overexpressed on the surface of human PC cells with restricted expression in normal tissues, enabling ICAM1 antibody to selectively recognize and target PC tumors in vivo. It is further demonstrated that the developed ICAM1 ADC induces potent and durable tumor regression in an orthotopic PC mouse model. To build a precision medicine, an MRI-based molecular imaging approach is developed that noninvasively maps the tumoral ICAM1 expression that can be potentially used to identify ICAM1-overexpressing PC patients. Collectively, this study establishes a strong foundation for the development of a promising ADC to address the critical need in the PC patient care.
由于缺乏有效的治疗方式，胰腺癌（PC）患者的预后仍然非常差，5年生存率不到8%。在此，开发了一种用于PC治疗的新型精准医学方法，该方法由一种合理设计的肿瘤靶向ICAM1抗体-药物偶联物（ADC）组成，其具有优化的化学连接子和细胞毒性载荷，并辅以基于磁共振成像（MRI）的分子成像方法，以无创评估ICAM1 ADC疗法的疗效。结果表明，ICAM1在人PC细胞表面差异过表达，在正常组织中表达受限，这使得ICAM1抗体能够在体内选择性识别并靶向PC肿瘤。进一步证明，所开发的ICAM1 ADC在原位PC小鼠模型中诱导了强大而持久的肿瘤消退。为了构建精准医学，开发了一种基于MRI的分子成像方法，该方法可以无创地绘制肿瘤ICAM1表达图谱，有可能用于识别ICAM1过表达的PC患者。总的来说，本研究为开发一种有前景的ADC奠定了坚实基础，以满足PC患者护理中的关键需求。
