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TU‐F‐12A‐01: 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
Author(s) -
Fung EK,
Cheal SM,
Chalasani S,
Fareedy SB,
Otto B,
Punzalan B,
Humm JL,
Bander NH,
Osborne JR,
Larson SM,
Zanzonico PB
Publication year - 2014
Publication title -
medical physics
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.473
H-Index - 180
eISSN - 2473-4209
pISSN - 0094-2405
DOI - 10.1118/1.4889356
Subject(s) - internalization , antigen , glutamate carboxypeptidase ii , monoclonal antibody , antibody , positron emission tomography , prostate cancer , chemistry , prostate specific antigen , prostate , kinetics , nuclear medicine , cancer research , cancer , medicine , cell , immunology , biochemistry , physics , quantum mechanics
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 8 9 Zr or 12 4 I, were prepared. 8 9 Zr 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 12 4 I‐J591 than for 8 9 Zr‐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 8 9 Zr or 12 4 I 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. 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).