Journal
MOLECULAR PHARMACEUTICS
Volume 11, Issue 11, Pages 3965-3973Publisher
AMER CHEMICAL SOC
DOI: 10.1021/mp500164r
Keywords
PSMA; PET; minibody; Cys-diabody; huJ591
Funding
- NIH MSKCC Center [P30-CA08748]
- National Cancer Institute, National Institutes of Health, Department of Health and Human Services [HHSN261201100123C]
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Engineered antibody fragments offer faster delivery with retained tumor specificity and rapid clearance from nontumor tissues. Here, we demonstrate that positron emission tomography (PET) based detection of prostate specific membrane antigen (PSMA) in prostatic tumor models using engineered bivalent antibodies built on single chain fragments (scFv) derived from the intact antibody, huJ591, offers similar tumor delineating properties but with the advantage of rapid targeting and imaging. Zr-89-radiolabeled huJ591 scFv (dimeric scFv-C(H)3; Zr-89-Mb) and cysteine diabodies (dimeric scFv; Zr-89-Cys-Db) demonstrated internalization and similar Kds (similar to 2 nM) compared to Zr-89-huJ591 in PSMA(+) cells. Tissue distribution assays established the specificities of both Zr-89-Mb and Zr-89-Cys-Db for PSMA(+) xenografts (6.2 +/- 2.5% ID/g and 10.2 +/- 3.4% ID/g at 12 h p.i. respectively), while minimal accumulation in PSMA(-) tumors was observed. From the PET images, Zr-89-Mb and Zr-89-Cys-Db exhibited faster blood clearance than the parent huJ591 while tumor-to-muscle ratios for all probes show comparable values across all time points. Ex vivo autoradiography and histology assessed the distribution of the probes within the tumor. Imaging PSMA-expressing prostate tumors with smaller antibody fragments offers rapid tumor accumulation and accelerated clearance; hence, shortened wait periods between tracer administration and high-contrast tumor imaging and lower dose-related toxicity are potentially realized.
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