Yasunaga Masahiro, Manabe Shino, Tsuji Atsushi, Furuta Mamoru, Ogata Koretsugu, Koga Yoshikatsu, Fujiwara Yuki, Saga Tsuneo, Matsumura Yasuhiro
Division of Developmental Therapeutics, EPOC, National Cancer Center.
Synthetic Cellular Chemistry Laboratory, RIKEN.
Yakugaku Zasshi. 2017;137(5):535-544. doi: 10.1248/yakushi.16-00255-3.
Antibody-drug conjugates (ADCs) comprise an antibody, a linker, and a drug or payload. The selection of a tumor-specific antibody and development of a linker having an efficient controlled drug release (CDR) are critical steps in developing a fully functional and effective ADC. In our research strategy, molecular imaging technologies have been employed to evaluate the efficiency of antibody delivery and CDR of the linker. In preclinical setting, antibody delivery into the tumor area or antibody penetration through the tumor stroma in malignant lymphoma or pancreatic tumor was evaluated by in vivo fluorescence imaging technique. Positron emission tomography (PET) imaging studies were conducted using Zr-labeled antibody to evaluate tumor targeting in a spontaneous carcinogenesis model. The model had dense stroma and was pathophysiologically very similar to human cancer. The drug imaging system, using microscopic mass spectroscopy (MMS) with enhanced resolution and sensitivity, was used for the evaluation of CDR. Paclitaxel (PTX)-incorporated micelle, a high-molecular-weight (HMW) carrier with CDR, showing similar properties as those of ADC, was analyzed. In contrast to free PTX, micelle selectively increased drug accumulation into the tumor and reduced toxicity in normal tissues by the enhanced permeability and retention (EPR) effect. Our drug imaging system has been used recently to evaluate the CDR of the ADC-linker. We present our work on the development of ADC using a molecular imaging technique.
抗体药物偶联物（ADC）由抗体、连接子和药物或有效载荷组成。选择肿瘤特异性抗体以及开发具有高效可控药物释放（CDR）的连接子是开发功能完备且有效的ADC的关键步骤。在我们的研究策略中，分子成像技术已被用于评估抗体递送效率和连接子的CDR。在临床前研究中，通过体内荧光成像技术评估抗体递送至肿瘤区域的情况，或评估抗体在恶性淋巴瘤或胰腺肿瘤中穿透肿瘤基质的情况。使用锆标记的抗体进行正电子发射断层扫描（PET）成像研究，以评估自发致癌模型中的肿瘤靶向性。该模型具有致密的基质，在病理生理上与人类癌症非常相似。使用具有更高分辨率和灵敏度的显微质谱（MMS）的药物成像系统用于评估CDR。分析了载有紫杉醇（PTX）的胶束，这是一种具有CDR的高分子量（HMW）载体，表现出与ADC相似的特性。与游离PTX相比，胶束通过增强的渗透和滞留（EPR）效应选择性地增加了药物在肿瘤中的积累，并降低了在正常组织中的毒性。我们的药物成像系统最近已用于评估ADC连接子的CDR。我们展示了我们使用分子成像技术开发ADC的工作。
