Recently, Professor Jeremiah A. Johnson from the Massachusetts Institute of Technology and his research team proposed a targeted cancer therapy using antibody–bottlebrush prodrug conjugates(Antibody-Bottlebrush Prodrug Conjugates, ABC). This research was published in the international academic journal Nature Biotechnology on September 9, 2025. A summary of this article and expert/editorial opinions were also published in the same issue.
Antibody–drug conjugates (ADCs) are effective targeted therapeutic agents, but they are limited in their ability to integrate less potent payloads, various drug mechanisms of action, different drug release mechanisms, and tunable drug–antibody ratios. Here, we introduce a technology called “antibody–bottlebrush prodrug conjugates” (ABCs) to overcome these limitations. An ABC consists of an IgG1 monoclonal antibody covalently linked to the terminus of a compact bivalent bottlebrush prodrug, which has payloads fixed through cleavable linkers and polyethylene glycol branches. This design allows for the synthesis of ABCs with tunable average drug–antibody ratios that are two orders of magnitude higher than those of traditional ADCs. We demonstrate the functional flexibility and manufacturing efficiency of this technology by synthesizing more than 10 different ABCs targeting HER2 or MUC1, using drugs with potencies spanning several orders of magnitude, as well as imaging agents for ABC visualization and photocatalysts for proximity-based labeling of the ABC interactome. Compared to conventional HER2-targeted ADCs, ABCs exhibit higher target engagement, higher cell uptake, and improved efficacy in tumor models, suggesting promise for clinical translation.
Appendix: English Abstract
Title: Antibody–bottlebrush prodrug conjugates for targeted cancer therapy
Author: Liu, Bin, Nguyen, Hung V.-T., Jiang, Yivan, Wang, Aiden X., Lensch, Valerie, Sun, Zehao, Boyer, Zane H., Raftopoulos, Philip A., Dai, Yutong, MacNicol, Piper L., Wang, Yuyan, Jyotsana, Nidhi, Wang, Wencong, Bhagchandani, Sachin, Hemdev, Sanjana, Shieh, Peyton, Kristufek, Samantha L., Boucher, Magalie, Downes, Michael, Evans, Ronald M., MacMillan, David W. C., Johnson, Jeremiah A.
Issue&Volume: 2025-09-09
Abstract: Antibody–drug conjugates (ADCs) are effective targeted therapeutics but are limited in their ability to incorporate less-potent payloads, varied drug mechanisms of action, different drug release mechanisms and tunable drug-to-antibody ratios. Here we introduce a technology to overcome these limitations called ‘antibody–bottlebrush prodrug conjugates’ (ABCs). An ABC consists of an IgG1 monoclonal antibody covalently conjugated to the terminus of a compact bivalent bottlebrush prodrug that has payloads bound through cleavable linkers and polyethylene glycol branches. This design enables the synthesis of ABCs with tunable average drug-to-antibody ratios up to two orders of magnitude greater than those of traditional ADCs. We demonstrate the functional flexibility and manufacturing efficiency of this technology by synthesizing more than 10 different ABCs targeting either HER2 or MUC1 using drugs with potencies spanning several orders of magnitude as well as imaging agents for ABC visualization and photocatalysts for proximity-based labeling of the ABC interactome. ABCs display high target engagement, high cell uptake and improved efficacy in tumor models compared to conventional HER2-targeted ADCs, suggesting promise for clinical translation.
Link to the full original article:
DOI：https://doi.org/10.1038/s41587-025-02772-z
Link to the summary article of this paper
DOI：https://doi.org/10.1038/s41587-025-02773-y
Journal Information
Nature Biotechnology：《自然—生物技术》Official website:https://www.nature.com/nbt/
This article is based on the original abstract, AI translation, and all citations are noted.