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Updated: Jun 12, 2025
An Orthotopic Resectional Mouse Model of Pancreatic Cancer
Published on: September 24, 2020
Anti-tissue factor antibody conjugated with monomethyl auristatin E or deruxtecan in pancreatic cancer models
Ryo Tsumura1, Takahiro Anzai1,2, Yoshikatsu Koga1
1Division of Developmental Therapeutics, EPOC, National Cancer Center, Kashiwa, Japan.
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.
Insights
Payload choice for antibody-drug conjugates (ADCs) targeting tissue factor (TF) impacts efficacy. Deruxtecan (DXd)-ADCs may offer better pancreatic cancer treatment due to heterogeneous TF expression, unlike MMAE-ADCs.
Area of Science:
- Oncology
- Pharmacology
- Biotechnology
Background:
- Antibody-drug conjugates (ADCs) are a promising cancer therapy class.
- Tissue factor (TF) is implicated in cancer, with anti-TF ADCs showing clinical utility.
- Payload optimization is crucial for ADC efficacy, yet comparisons of different cytotoxic mechanisms are lacking.
Purpose of the Study:
- To compare the efficacy of anti-TF ADCs with different payloads (MMAE and DXd) in pancreatic cancer models.
- To investigate the influence of TF expression levels and heterogeneity on ADC response.
- To determine optimal payload selection strategies for anti-TF ADCs.
Main Methods:
- Humanized anti-TF antibody (clone.1084) conjugated with either MMAE or DXd.
- Evaluation of ADC efficacy in pancreatic cancer cell line and patient-derived xenograft models.
- Analysis of TF expression in pancreatic cancer tissue array.
Main Results:
- Optimizing the drug-to-antibody ratio was essential for each payload to ensure pharmacokinetics and delivery.
- Anti-TF ADC with MMAE demonstrated superior efficacy in tumors with strong, homogeneous TF expression.
- Anti-TF ADC with DXd showed greater effectiveness in tumors with weak, heterogeneous TF expression, common in pancreatic cancer.
Conclusions:
- Payload selection for anti-TF ADCs should be tailored to TF expression patterns.
- DXd-conjugated anti-TF ADCs may be more suitable for pancreatic cancer treatment due to prevalent weak and heterogeneous TF expression.
- Individualized optimization of ADC payloads holds potential for maximizing therapeutic outcomes.
