Anti-tissue factor antibody conjugated with monomethyl auristatin E or deruxtecan in pancreatic cancer models.

IF 5.7 2区 医学 Q1 Medicine Cancer Science Pub Date : 2024-09-25 DOI:10.1111/cas.16335
Ryo Tsumura, Takahiro Anzai, Yoshikatsu Koga, Hiroki Takashima, Yasuhiro Matsumura, Masahiro Yasunaga
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Abstract

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.

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在胰腺癌模型中使用与单甲基金丝桃素 E 或德鲁替康结合的抗组织因子抗体。
抗体药物共轭物(ADCs)已被公认为是一类很有前景的癌症治疗药物。组织因子(TF)是血液凝固通路的启动因子,人们一直在研究它与癌症的关系,一些临床前和临床研究提供了抗TF ADCs的数据,包括2021年获批的tisotumab vedotin。然而,其他有效载荷在抗TF ADC设计中的可行性仍不清楚,因为没有报告对具有不同细胞毒性机制的有效载荷进行了比较。对于靶向 Her2 等其他抗原的 ADC,优化有效载荷也是提高体内疗效的一个重要问题。在这项研究中,我们制备了与单甲基乌司他丁 E(MMAE)或德克替康(DXd)共轭的人源化抗-TF Ab(clone.1084),并评估了其在多种胰腺癌细胞系和患者来源异种移植模型中的疗效。因此,有必要优化每种有效载荷的药物/抗体比例,以防止药代动力学恶化并最大限度地提高递送效率。此外,MMAE共轭的抗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共轭的抗TF ADC在TF表达弱且不均匀的肿瘤中更有效。对胰腺癌组织阵列的分析表明,大多数TF阳性标本的TF表达较弱且不均匀,这表明DXd-结合型抗TF ADC对胰腺癌的反应率可能高于MMAE-结合型抗TF ADC。尽管如此,我们的研究结果表明,对每位患者的 ADC 有效载荷进行单独优化可最大限度地发挥 ADC 疗法的潜力。
本文章由计算机程序翻译,如有差异,请以英文原文为准。
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来源期刊
Cancer Science
Cancer Science ONCOLOGY-
CiteScore
9.90
自引率
3.50%
发文量
406
审稿时长
17 weeks
期刊介绍: Cancer Science (formerly Japanese Journal of Cancer Research) is a monthly publication of the Japanese Cancer Association. First published in 1907, the Journal continues to publish original articles, editorials, and letters to the editor, describing original research in the fields of basic, translational and clinical cancer research. The Journal also accepts reports and case reports. Cancer Science aims to present highly significant and timely findings that have a significant clinical impact on oncologists or that may alter the disease concept of a tumor. The Journal will not publish case reports that describe a rare tumor or condition without new findings to be added to previous reports; combination of different tumors without new suggestive findings for oncological research; remarkable effect of already known treatments without suggestive data to explain the exceptional result. Review articles may also be published.
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