Program Information

Quantitative Non-Linear Compartment Modeling of ⁸⁹Zr- and ¹²⁴I-Labeled J591 Monoclonal Antibody Kinetics Using Serial Non-Invasive Positron Emission Tomography Imaging in a Pre-Clinical Human Prostate Cancer Mouse Model

E Fung

EK Fung¹*, SM Cheal¹ , S Chalasani¹ , SB Fareedy¹ , B Otto² , B Punzalan¹ , JL Humm¹ , NH Bander² , JR Osborne¹ , SM Larson¹ , PB Zanzonico¹ , (1) Memorial Sloan Kettering Cancer Center, New York, New York, (2) Weill Cornell Medical College, New York, New York

Presentations

TU-F-12A-1 Tuesday 4:30PM - 6:00PM Room: 12A

Purpose:
To examine the binding kinetics of human IgG monoclonal antibody J591 which targets prostate-specific membrane antigen (PSMA) in a pre-clinical mouse cancer model using quantitative PET compartmental analysis of two radiolabeled variants.

Methods:
PSMA is expressed in normal human prostate, and becomes highly upregulated in prostate cancer, making it a promising therapeutic target. Two forms of J591, radiolabeled with either ⁸⁹Zr or ¹²⁴I, were prepared. ⁸⁹Zr is a radiometal that becomes trapped in the cell upon internalization by the antigen-antibody complex, while radioiodine leaves the cell. Mice with prostate cancer xenografts underwent non-invasive serial imaging on a Focus 120 microPET up to 144 hours post-injection of J591. A non-linear compartmental model describing the binding and internalization of antibody in tumor xenograft was developed and applied to the PET-derived time-activity curves. The antibody-antigen association rate constant (ka), total amount of antigen per gram tumor (Ag_total), internalization rate of antibody-antigen complex, and efflux rate of radioisotope from tumor were fitted using the model. The surface-bound and the internalized activity were also estimated.

Results:
Values for ka, Ag_total, and internalization rate were found to be similar regardless of radiolabel payload used. The efflux rate, however, was ~ 9-fold higher for ¹²⁴I-J591 than for ⁸⁹Zr-J591. Time-dependent surface-bound and internalized radiotracer activity were similar for both radiolabels at early times post-injection, but clearly differed beyond 24 hours.

Conclusion:
Binding and internalization of J591 to PSMA-expressing tumor xenografts were similar when radiolabeled with either ⁸⁹Zr or ¹²⁴I payload. The difference in efflux of radioactivity from tumor may be attributable to differential biological fate intracellularly of the radioisotopes. This has great significance for radioimmunotherapy and antibody-drug conjugates. Further exploration using the model will examine binding and radioisotope residence as antibody dose is increased to antigen saturation.


Funding Support, Disclosures, and Conflict of Interest: The Center for Targeted Radioimmunotherapy and Theranostics, Ludwig Center for Cancer Immunotherapy, Memorial Sloan Kettering Cancer Center (MSK), NIH (R25-CA096945). Technical services provided by the MSK Small-Animal Imaging Core Facility were supported by the NIH (R24-CA83084, P30-CA08748, and P50-CA92629; Zanzonico). NCI, Center to Reduce Cancer Health Disparity (R21 CA153177-03; Osborne).


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