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

Autor: Tsumura R; Division of Developmental Therapeutics, EPOC, National Cancer Center, Kashiwa, Japan., Anzai T; 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., Koga Y; Division of Developmental Therapeutics, EPOC, National Cancer Center, Kashiwa, Japan., Takashima H; Division of Developmental Therapeutics, EPOC, National Cancer Center, Kashiwa, Japan., Matsumura Y; Department of Immune Medicine, National Cancer Center Research Institute, Tokyo, Japan.; Research Division, RIN Institute Inc., Tokyo, Japan., Yasunaga M; Division of Developmental Therapeutics, EPOC, National Cancer Center, Kashiwa, Japan.
Jazyk: angličtina
Zdroj: Cancer science [Cancer Sci] 2024 Dec; Vol. 115 (12), pp. 3986-3996. Date of Electronic Publication: 2024 Sep 25.
DOI: 10.1111/cas.16335
Abstrakt: 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.
(© 2024 The Author(s). Cancer Science published by John Wiley & Sons Australia, Ltd on behalf of Japanese Cancer Association.)
Databáze: MEDLINE
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