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Imaging small human prostate cancer xenografts after pretargeting with bispecific bombesin-antibody complexes and targeting with high specific radioactivity labeled polymer-drug conjugates

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European Journal of Nuclear Medicine and Molecular Imaging Aims and scope Submit manuscript

Abstract

Purpose

Pretargeting with bispecific monoclonal antibodies (bsMAb) for tumor imaging was developed to enhance target to background activity ratios. Visualization of tumors was achieved by the delivery of mono- and divalent radiolabeled haptens. To improve the ability to image tumors with bsMAb, we have combined the pretargeting approach with targeting of high specific activity radiotracer labeled negatively charged polymers. The tumor antigen-specific antibody was replaced with bombesin (Bom), a ligand that binds specifically to the growth receptors that are overexpressed by many tumors including prostate cancer. Bom-anti-diethylenetriaminepentaacetic acid (DTPA) bispecific antibody complexes were used to demonstrate pretargeting and imaging of very small human prostate cancer xenografts targeted with high specific activity 111In- or 99mTc-labeled negatively charged polymers.

Methods

Bispecific antibody complexes consisting of intact anti-DTPA antibody or Fab′ linked to Bom via thioether bonds (Bom-bsCx or Bom-bsFCx, respectively) were used to pretarget PC-3 human prostate cancer xenografts in SCID mice. Negative control mice were pretargeted with Bom or anti-DTPA Ab. 111In-Labeled DTPA-succinyl polylysine (DSPL) was injected intravenously at 24 h (7.03 ± 1.74 or 6.88 ± 1.89 MBq 111In-DSPL) after Bom-bsCx or 50 ± 5.34 MBq of 99mTc-DSPL after Bom-bsFCx pretargeting, respectively. Planar or single photon emission computed tomography (SPECT)/CT gamma images were obtained for up to 3 h and only planar images at 24 h. After imaging, all mice were killed and biodistribution of 111In or 99mTc activities were determined by scintillation counting.

Results

Both planar and SPECT/CT imaging enabled detection of PC-3 prostate cancer lesions less than 1–2 mm in diameter in 1–3 h post 111In-DSPL injection. No lesions were visualized in Bom or anti-DTPA Ab pretargeted controls. 111In-DSPL activity in Bom-bsCx pretargeted tumors (1.21 ± 0.36%ID/g) was 5.4 times that in tumors pretargeted with Bom or anti-DTPA alone (0.22 ± 0.08, p = 0.001). PC-3 xenografts pretargeted with Bom-bsFCx and targeted with 99mTc-DSPL were visualizable by 1–3 h. Exquisite tumor uptake at 24 h (6.54 ± 1.58%ID/g) was about 15 times greater than that of Bom pretargeted controls (0.44 ± 0.17, p = 0.002).

Conclusion

Pretargeting prostate cancer with Bom-bsCx or Bom-bsFCx enabled fast delivery of high specific radioactivity 111In- or 99mTc-labeled polymer-drug conjugates resulting in visualization of lesions smaller than 1–2 mm in diameter within 3 h.

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Conflicts of interest

This research was partially support by an unrestricted grant from Gwathmey Inc., Cambridge, MA, USA. BAK is a cofounder of Akrivis Technologies, LLC which is interested in licensing the technology developed at the university. All other authors have no conflict of interest to declare related to this work.

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Correspondence to Ban-An Khaw.

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Patil, V., Gada, K., Panwar, R. et al. Imaging small human prostate cancer xenografts after pretargeting with bispecific bombesin-antibody complexes and targeting with high specific radioactivity labeled polymer-drug conjugates. Eur J Nucl Med Mol Imaging 39, 824–839 (2012). https://doi.org/10.1007/s00259-011-2050-3

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  • DOI: https://doi.org/10.1007/s00259-011-2050-3

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