Noninvasive quantification of target availability during therapy using paired-agent fluorescence tomography

Area of Science:

• Oncology
• Medical Imaging
• Pharmacodynamics

Background:

• Immuno-oncology therapies targeting tumor receptor profiles are crucial but assessing receptor availability (RA) and drug-target engagement is challenging.
• Current imaging strategies struggle with nonspecific uptake of imaging agents, hindering accurate assessment of therapeutic efficacy.
• Epidermal growth factor receptor (EGFR) is a key target in various cancers, making its assessment vital for treatment.

Purpose of the Study:

• To evaluate the capability of MRI-coupled paired-agent fluorescence tomography (MRI-PAFT) for rapid, quantitative assessment of EGFR availability.
• To determine if MRI-PAFT can assess EGFR availability in response to anti-EGFR antibody therapy in orthotopic brain tumor models.
• To assess the utility of a simplified 'snapshot' approach within MRI-PAFT for quantifying drug-receptor engagement.

Main Methods:

• Mice with orthotopic brain tumors (EGFR-high U251, EGFR-undetectable 9L) were treated with cetuximab or left untreated.
• All animals underwent MRI-PAFT immediately after paired-agent administration.
• Receptor availability (RA) values were calculated using a model-based dynamic approach and a simplified two-timepoint 'snapshot' approach.

Main Results:

• MRI-PAFT significantly differentiated RA between treated and untreated EGFR(+) tumors (p=0.027, AUC-ROC=0.92).
• No significant difference in RA was observed in EGFR(-) tumors (p=0.89, AUC-ROC=0.55).
• The snapshot approach quantified drug-receptor engagement within 30 minutes; targeted agent alone did not distinguish tumors.

Conclusions:

• Noninvasive MRI-PAFT enables rapid quantification of receptor availability and drug-target engagement in response to therapy.
• This imaging strategy holds potential for preclinical drug development, patient stratification, and treatment monitoring.
• The simplified snapshot approach offers a rapid method for assessing drug-receptor interactions.