Increased Tumor Penetration of Single-Domain Antibody–Drug Conjugates Improves In Vivo Efficacy in Prostate Cancer Models
| Autor: | Thomas Sandal, Ian Nessler, Steven Vance, Thomas A. Keating, Anna Kopp, Lorraine Thompson, Eshita Khera, Adnan O. Abu-Yousif, Qifeng Qiu, Greg M. Thurber, Normann Goodwin, James Legg |
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| Rok vydání: | 2020 |
| Předmět: |
0301 basic medicine
Cancer Research Biodistribution Chemistry media_common.quotation_subject In vitro 03 medical and health sciences 030104 developmental biology 0302 clinical medicine Cell killing Oncology Pharmacokinetics In vivo Cell culture 030220 oncology & carcinogenesis Cancer research Potency Internalization media_common |
| Zdroj: | Cancer Research. 80:1268-1278 |
| ISSN: | 1538-7445 0008-5472 |
| DOI: | 10.1158/0008-5472.can-19-2295 |
| Popis: | Targeted delivery of chemotherapeutics aims to increase efficacy and lower toxicity by concentrating drugs at the site-of-action, a method embodied by the seven current FDA-approved antibody–drug conjugates (ADC). However, a variety of pharmacokinetic challenges result in relatively narrow therapeutic windows for these agents, hampering the development of new drugs. Here, we use a series of prostate-specific membrane antigen–binding single-domain (Humabody) ADC constructs to demonstrate that tissue penetration of protein–drug conjugates plays a major role in therapeutic efficacy. Counterintuitively, a construct with lower in vitro potency resulted in higher in vivo efficacy than other protein–drug conjugates. Biodistribution data, tumor histology images, spheroid experiments, in vivo single-cell measurements, and computational results demonstrate that a smaller size and slower internalization rate enabled higher tissue penetration and more cell killing. The results also illustrate the benefits of linking an albumin-binding domain to the single-domain ADCs. A construct lacking an albumin-binding domain was rapidly cleared, leading to lower tumor uptake (%ID/g) and decreased in vivo efficacy. In conclusion, these results provide evidence that reaching the maximum number of cells with a lethal payload dose correlates more strongly with in vivo efficacy than total tumor uptake or in vitro potency alone for these protein–drug conjugates. Computational modeling and protein engineering can be used to custom design an optimal framework for controlling internalization, clearance, and tissue penetration to maximize cell killing. Significance: A mechanistic study of protein–drug conjugates demonstrates that a lower potency compound is more effective in vivo than other agents with equal tumor uptake due to improved tissue penetration and cellular distribution. |
| Databáze: | OpenAIRE |
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