Methods and compositions for noninvasive detection of organ transplant rejection
Inventors
Kwong, Gabriel A. • Adams, Andrew B. • Mac, Quoc • Mathews, David V.
Assignees
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Publication Number
US-12692533-B2
Publication Date
2026-07-28
Expiration Date
Abstract
An activity-based nanosensor composition for detecting protease activity comprising a cleavable detectable substrate and methods of use are disclosed.
Core Innovation
The activity-based nanosensor comprises a scaffold, a Granzyme B-cleavable peptide substrate, and a detectable reporter coupled to the scaffold by the substrate. In vivo cleavage releases the reporter from the scaffold into circulation, where it accumulates in bodily fluids. Measuring reporter levels in a blood or urine sample indicates a T cell cytotoxicity driven immune condition or likelihood thereof, and the method includes treating the subject when reporter is detected.
The technology enables noninvasive detection and monitoring of T-cell cytotoxicity and acute or chronic transplant rejection. Disclosures demonstrate substrate specificity for Granzyme B over coagulation and complement proteases and sensing of alloreactive T-cell killing. In a mouse skin-allograft model, urinary reporter signals increase more than twofold at acute rejection onset before graft scores distinguish rejection, yielding a receiver operating characteristic area under the curve of approximately 0.97.
Claims Coverage
The claims identify one independent claim directed to detecting a T cell cytotoxicity driven immune condition and treating the subject, comprising three inventive features.
Granzyme B-cleavable peptide substrate nanosensor
The nanosensor comprises a scaffold, a peptide substrate coupled to the scaffold and capable of being cleaved by Granzyme B, and a detectable reporter coupled to the scaffold by the peptide substrate.
Reporter release and detection in a subject sample
In vivo cleavage of the peptide substrate releases the detectable reporter from the scaffold into circulation, wherein reporter detection in a blood or urine sample indicates that the subject has or is likely to have a T cell cytotoxicity driven immune condition.
Subject treatment upon reporter detection
The method includes treating the subject for the T cell cytotoxicity driven immune condition when the detectable reporter is detected.
Claim 1 combines a Granzyme B-cleavable nanosensor with reporter detection in blood or urine to indicate a T cell cytotoxicity driven immune condition or its likelihood, followed by treating the subject when reporter is detected.
Stated Advantages
The nanosensor enables noninvasive detection and monitoring through urinary reporter signals.
In a mouse skin-allograft model, urinary reporter signals rose more than twofold at acute rejection onset before graft scores distinguished rejection, differentiating rejecting allografts from accepting isografts with an area under the curve of 0.969.
Documented Applications
Detection and monitoring of T-cell cytotoxicity and acute or chronic transplant rejection, including acute cellular rejection in a mouse skin-allograft model.
Detection and monitoring of other T-cell cytotoxicity-related conditions and protease targets.
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