Tsumura Ryo, Anzai Takahiro, Koga Yoshikatsu, Takashima Hiroki, Matsumura Yasuhiro, Yasunaga Masahiro
Division of Developmental Therapeutics, EPOC, National Cancer Center, Kashiwa, Japan.
Department of Chemistry and Materials Science, National Institute of Technology (KOSEN), Gunma College, Maebashi, Japan.
Cancer Sci. 2024 Dec;115(12):3986-3996. doi: 10.1111/cas.16335. Epub 2024 Sep 25.
Antibody-drug conjugates (ADCs) have been recognized as a promising class of cancer therapeutics. Tissue factor (TF), an initiator of the blood coagulation pathway, has been investigated regarding its relationship with cancer, and several preclinical and clinical studies have presented data on anti-TF ADCs, including tisotumab vedotin, which was approved in 2021. However, the feasibility of other payloads in the design of anti-TF ADCs is still unclear because no reports have compared payloads with different cytotoxic mechanisms. For ADCs targeting other antigens, such as Her2, optimizing the payload is also an important issue in order to improve in vivo efficacy. In this study, we prepared humanized anti-TF Ab (clone.1084) conjugated with monomethyl auristatin E (MMAE) or deruxtecan (DXd), and evaluated the efficacy in several cell line- and patient-derived xenograft models of pancreatic cancer. As a result, optimizing the drug / Ab ratio was necessary for each payload in order to prevent pharmacokinetic deterioration and maximize delivery efficiency. In addition, MMAE-conjugated anti-TF ADC showed higher antitumor effects in tumors with strong and homogeneous TF expression, while DXd-conjugated anti-TF ADC was more effective in tumors with weak and heterogeneous TF expression. Analysis of a pancreatic cancer tissue array showed weak and heterogeneous TF expression in most TF-positive specimens, indicating that the response rate to pancreatic cancer might be higher for DXd- than MMAE-conjugated anti-TF ADC. Nevertheless, our findings indicated that optimizing the ADC payloads individually in each patient could maximize the potential of ADC therapeutics.
抗体药物偶联物（ADCs）已被公认为一类很有前景的癌症治疗药物。组织因子（TF）是血液凝固途径的启动因子，人们对其与癌症的关系进行了研究，多项临床前和临床研究提供了关于抗TF ADC的数据，包括2021年获批的替索单抗（tisotumab vedotin）。然而，由于尚无报告比较具有不同细胞毒性机制的载药，抗TF ADC设计中其他载药的可行性仍不明确。对于靶向其他抗原（如Her2）的ADCs，优化载药也是提高体内疗效的一个重要问题。在本研究中，我们制备了与单甲基奥瑞他汀E（MMAE）或德卢替康（DXd）偶联的人源化抗TF抗体（克隆号1084），并在多种细胞系和患者来源的胰腺癌异种移植模型中评估了其疗效。结果表明，为防止药代动力学恶化并最大化递送效率，每种载药都需要优化药物/抗体比例。此外，MMAE偶联的抗TF ADC在TF表达强且均匀的肿瘤中显示出更高的抗肿瘤效果，而DXd偶联的抗TF ADC在TF表达弱且异质性的肿瘤中更有效。对胰腺癌组织芯片的分析显示，大多数TF阳性标本中TF表达弱且异质性，这表明DXd偶联的抗TF ADC对胰腺癌的反应率可能高于MMAE偶联的抗TF ADC。尽管如此，我们的研究结果表明，在每个患者中单独优化ADC载药可最大化ADC治疗的潜力。
