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A Rationally Designed ICAM1 Antibody Drug Conjugate for Pancreatic Cancer
Advanced Science ( IF 14.3 ) Pub Date : 2020-11-03 , DOI: 10.1002/advs.202002852 Jing Huang 1, 2 , Agoston T Agoston 3 , Peng Guo 1, 2 , Marsha A Moses 1, 2
Advanced Science ( IF 14.3 ) Pub Date : 2020-11-03 , DOI: 10.1002/advs.202002852 Jing Huang 1, 2 , Agoston T Agoston 3 , Peng Guo 1, 2 , Marsha A Moses 1, 2
Affiliation
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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.
中文翻译：
合理设计的 ICAM1 抗体药物偶联物用于治疗胰腺癌
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 年生存率低于 8%。这里，开发了一种用于 PC 治疗的新型精准医学方法，该方法由合理设计的肿瘤靶向 ICAM1 抗体药物偶联物（ADC）组成，具有优化的化学接头和细胞毒性有效负载，并辅以基于磁共振成像（MRI）的分子成像方法无创评估 ICAM1 ADC 治疗的效率。结果表明，ICAM1 在人 PC 细胞表面差异性过表达，而在正常组织中表达受限，使得 ICAM1 抗体能够在体内选择性识别和靶向 PC 肿瘤。进一步证明，开发的 ICAM1 ADC 在原位 PC 小鼠模型中诱导有效且持久的肿瘤消退。为了构建精准医疗，开发了一种基于 MRI 的分子成像方法，该方法可无创地绘制肿瘤 ICAM1 表达图谱，可用于识别 ICAM1 过度表达的 PC 患者。总的来说，这项研究为开发有前景的 ADC 奠定了坚实的基础，以满足 PC 患者护理的关键需求。
更新日期：2020-12-16
中文翻译：
合理设计的 ICAM1 抗体药物偶联物用于治疗胰腺癌
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 年生存率低于 8%。这里，开发了一种用于 PC 治疗的新型精准医学方法，该方法由合理设计的肿瘤靶向 ICAM1 抗体药物偶联物（ADC）组成，具有优化的化学接头和细胞毒性有效负载，并辅以基于磁共振成像（MRI）的分子成像方法无创评估 ICAM1 ADC 治疗的效率。结果表明，ICAM1 在人 PC 细胞表面差异性过表达，而在正常组织中表达受限，使得 ICAM1 抗体能够在体内选择性识别和靶向 PC 肿瘤。进一步证明，开发的 ICAM1 ADC 在原位 PC 小鼠模型中诱导有效且持久的肿瘤消退。为了构建精准医疗，开发了一种基于 MRI 的分子成像方法，该方法可无创地绘制肿瘤 ICAM1 表达图谱，可用于识别 ICAM1 过度表达的 PC 患者。总的来说，这项研究为开发有前景的 ADC 奠定了坚实的基础，以满足 PC 患者护理的关键需求。
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