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Bispecific Antibody Pretargeting PET (ImmunoPET) with an ¹²⁴I-Labeled Hapten-Peptide

¹ Immunomedics, Inc., Morris Plains, New Jersey; ² Department of Medical Physics, Memorial Sloan-Kettering Cancer Center, New York, New York; ³ Center for Molecular Medicine and Immunology, Belleville, New Jersey; ⁴ IBC Pharmaceuticals, Inc., Morris Plains, New Jersey; and ⁵ Nuclear Medicine, Memorial Sloan-Kettering Cancer Center, New York, New York

Correspondence: For correspondence or reprints contact: Robert M. Sharkey, PhD, Center for Molecular Medicine and Immunology, 520 Belleville Ave, Belleville, NJ 07109. E-mail: rmsharkey{at}gscancer.org.

We previously described a highly flexible bispecific antibody (bs-mAb) pretargeting procedure using a multivalent, recombinant anti-CEA (carcinoembryonic antigen) x anti-HSG (histamine-succinyl-glycine) fusion protein with peptides radiolabeled with ¹¹¹In, ⁹⁰Y, ¹⁷⁷Lu, and ^99mTc. The objective of this study was to develop a radioiodination procedure primarily to assess PET imaging with ¹²⁴I. Methods: A new peptide, DOTA-D-Tyr-D-Lys(HSG)-D-Glu-D-Lys(HSG)-NH₂ (DOTA is 1,4,7,10-tetraazacyclododecane-N,N',N'',N'''-tetraacetic acid), was synthesized and conditions were established for radioiodination with yields of 70% for ¹³¹I and 60% for ¹²⁴I. Pretargeting with the ¹³¹I- and ¹²⁴I-labeled peptide was tested in nude mice bearing LS174T human colonic tumors that were first given the anti-CEA x anti-HSG bs-mAb. Imaging (including small-animal PET) and necropsy data were collected at several intervals over 24 h. Comparisons were made between animals given ¹²⁴I-anti-CEA Fab', ¹⁸F-FDG, the same peptide radiolabeled with ¹¹¹In and pretargeted with the bs-mAb, and the radioiodinated peptide alone. Results: The radioiodinated peptide alone cleared quickly from the blood with no evidence of tumor targeting, but when pretargeted with the bs-mAb, tumor uptake increased 70-fold, with efficient and rapid clearance from normal tissues, allowing clear visualization of tumor within 1–2 h. Tumor uptake measured at necropsy was 3- to 15-fold higher and tumor-to-blood ratios were 10- to 20-fold higher than those for ¹²⁴I-Fab' at 1 and 24 h, respectively. Thyroid and stomach uptake was observed with the radioiodinated peptide several hours after injection (animals were not premedicated to reduce uptake in these tissues), but gastric uptake was much more pronounced with ¹²⁴I-Fab'. Tumor visualization with ¹⁸F-FDG at 1.5 h was also good but showed substantially more uptake in several normal tissues, making image interpretation in the pretargeted animals less ambiguous than with ¹⁸F-FDG. Conclusion: Bispecific antibody pretargeting has a significant advantage for tumor imaging over directly radiolabeled antibodies and could provide additional enhancements for oncologic imaging, particularly for improving targeting specificity as compared with ¹⁸F-FDG.

Key Words: pretargeting • bispecific antibody • PET • radioiodination • peptides • colon cancer

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