Small molecules for dual function positron emission tomography (PET) and cell suicide switches
Inventors
FARWELL, Michael • SELLMYER, Mark • LOHITH, Katheryn M.
Assignees
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Publication Number
US-12697403-B2
Publication Date
2026-08-04
Expiration Date
Abstract
The present invention includes an engineered cell comprising a chimeric antigen receptor (CAR) further comprising a nucleic acid molecule comprising a suicide gene comprising a ligand binding domain and a suicide domain wherein the ligand binding domain is capable of binding to radiolabeled tracer or a small molecule suicide switch. This invention also includes methods for inducing apoptosis of an engineered cell, methods for assessing the efficacy or toxicity of an adoptive cell therapy in a subject, methods for detecting the quantity of engineered T cells in a subject, methods for monitoring an immunotherapy treatment in a subject and methods of imaging engineered T cells in a subject. In some embodiments, the imaging is performed via Positron Emission Topography (PET). This invention further includes a chemical inducer of dimerization (CID), wherein the CID is a Bis-Trimethoprim (Bis-TMP).
Core Innovation
The disclosure describes engineered cells comprising a chimeric antigen receptor (CAR) and a nucleic acid molecule encoding a suicide gene. The suicide gene is expressed as a fusion protein that includes an E. coli dihydrofolate reductase (eDHFR) ligand binding domain and an inducible caspase 9 (iCasp9) suicide domain.
The fusion protein further comprises a linker consisting of 15 or 18 amino acids in length. The document describes a dual function suicide-reporter gene concept, where the suicide activity is linked to ligand binding for associated detection using radiolabeled tracers.
The disclosed approaches support assessment of engineered T cells, including CAR T cells, by combining a kill switch function with tracer-based readout. The description includes activation using a small-molecule dimerizer and evaluation of DHFR-iCasp9 activation with Bis-TMP compounds.
Claims Coverage
The independent claim set covers 1 independent claim, defining a CAR-engineered cell that includes a specific eDHFR-iCasp9 suicide fusion with a defined linker length. A dependent claim narrows the engineered cell to a T cell.
CAR and eDHFR-iCasp9 suicide fusion in an engineered cell
An engineered cell comprising a chimeric antigen receptor (CAR) and a nucleic acid molecule encoding a suicide gene that expresses a fusion protein comprising an E. coli dihydrofolate reductase (eDHFR) ligand binding domain and an inducible caspase 9 (iCasp9) domain.
15- or 18-amino-acid linker in the suicide fusion protein
The fusion protein further comprises a linker consisting of 15 or 18 amino acids in length.
T cell engineered cell type
The engineered cell is a T cell.
Overall, the claim coverage centers on CAR-containing engineered cells that express an eDHFR-iCasp9 suicide fusion protein, with the linkage between the eDHFR ligand binding domain and the iCasp9 suicide domain specifically defined as 15 or 18 amino acids, and a dependent claim specifying the engineered cell type as a T cell.
Stated Advantages
Provides a suicide-reporter gene concept combining a suicide function with reporter assessment via ligand-associated tracers.
Ability to induce apoptosis using a small-molecule dimerizer.
Use of PET imaging to assess efficacy and toxicity of adoptive cell therapy.
Ability to image and quantify engineered T cells and monitor immunotherapy treatment.
Documented Applications
PET imaging to detect and quantify engineered T cells.
Monitoring immunotherapy treatment using PET imaging.
Assessing efficacy and toxicity of adoptive cell therapy using imaging.
Inducing apoptosis for ablation via switching to a cold dimerized ligand.
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