Urinary detection of early responses to checkpoint blockade and of resistance to it via protease-cleaved antibody-conjugated sensors

• Type of Material: Article
• Authors: Quoc D Mac, Georgia Tech College of Engineering and Emory School of Medicine; Anirudh Sivakumar, Georgia Tech College of Engineering and Emory School of Medicine; Hathaichanok Phuengkham, Georgia Tech College of Engineering and Emory School of Medicine; Congmin Xu, Georgia Tech College of Engineering and Emory School of Medicine; James R Bowen, Georgia Tech College of Engineering and Emory School of Medicine; Fang-Yi Su, Georgia Tech College of Engineering and Emory School of Medicine; Samuel Z Stentz, Georgia Tech College of Engineering and Emory School of Medicine; Hyoungjun Sim, Georgia Tech College of Engineering and Emory School of Medicine; Adrian M Harris, Georgia Tech College of Engineering and Emory School of Medicine; Tonia T Li, Georgia Tech College of Engineering and Emory School of Medicine; Peng Qiu, Georgia Tech College of Engineering and Emory School of Medicine; Gabriel A Kwong, Emory University
• Language: English
• Date: 2022-03-03
• Publisher: NATURE PORTFOLIO
• Publication Version: Author Accepted Manuscript (After Peer Review)
• Copyright Statement: © 2022, The Author(s), under exclusive licence to Springer Nature Limited
• Final Published Version (URL): http://dx.doi.org/10.1038/s41551-022-00852-y
• Title of Journal or Parent Work: NATURE BIOMEDICAL ENGINEERING
• Volume: 6
• Issue: 3
• Start Page: 310
• End Page: +
• Grant/Funding Information: Q.D.M. and A.S. are supported by the NSF Graduate Research Fellowships Program (Grant No. DGE-1650044).; This work was funded by the NIH Director’s New Innovator Award DP2HD091793 and the National Cancer Institute R01 grant 5R01CA237210.
• Keywords: PEMBROLIZUMAB; TUMOR RESPONSE; Science & Technology; PREDICTIVE BIOMARKER; MOUSE; CD8(+) T-CELLS; CANCER; SUBSTRATE-SPECIFICITY; GRANZYME-B; PD-1; CLINICAL-RESPONSE; Engineering; Technology; Engineering, Biomedical

Abstract

Immune checkpoint blockade (ICB) therapy does not benefit the majority of treated patients, and those who respond to the therapy can become resistant to it. Here we report the design and performance of systemically administered protease activity sensors conjugated to anti-programmed cell death protein 1 (αPD1) antibodies for the monitoring of antitumour responses to ICB therapy. The sensors consist of a library of mass-barcoded protease substrates that, when cleaved by tumour proteases and immune proteases, are released into urine, where they can be detected by mass spectrometry. By using syngeneic mouse models of colorectal cancer, we show that random forest classifiers trained on mass spectrometry signatures from a library of αPD1-conjugated mass-barcoded activity sensors for differentially expressed tumour proteases and immune proteases can be used to detect early antitumour responses and discriminate resistance to ICB therapy driven by loss-of-function mutations in either the B2m or Jak1 genes. Biomarkers of protease activity may facilitate the assessment of early responses to ICB therapy and the classification of refractory tumours based on resistance mechanisms.