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A Novel Bispecific, Trivalent Antibody Construct for Targeting Pancreatic Carcinoma

¹ Garden State Cancer Center, Center for Molecular Medicine and Immunology, Belleville, New Jersey; ² IBC Pharmaceuticals, Inc.; and ³ Immunomedics, Inc., Morris Plains, New Jersey

Requests for reprints: David V. Gold, Garden State Cancer Center, 520 Belleville Avenue, Belleville, NJ 07109. Phone: 973-844-7025; Fax 1-973-844-7020; E-mail: dvgold{at}gscancer.org.

Key Words: Antibody • Imaging • Pancreatic Cancer

Preclinical and clinical studies have demonstrated the application of radiolabeled mAb-PAM4 for nuclear imaging and radioimmunotherapy of pancreatic carcinoma. We have now examined the ability of a novel PAM4-based, bispecific monoclonal antibody (mAb) construct, TF10, to pretarget a radiolabeled peptide for improved imaging and therapy. TF10 is a humanized, bispecific mAb, divalent for mAb-PAM4 and monovalent for mAb-679, reactive against the histamine-succinyl-glycine hapten. Biodistribution studies and nuclear imaging of the radiolabeled TF10 and/or TF10-pretargeted hapten-peptide (IMP-288) were conducted in nude mice bearing CaPan1 human pancreatic cancer xenografts. ¹²⁵I-TF10 cleared rapidly from the blood, with levels decreasing to <1% injected dose per gram (ID/g) by 16 hours. Tumor uptake was 3.47 ± 0.66% ID/g at this time point with no accumulation in any normal tissue. To show the utility of the pretargeting approach, ¹¹¹In-IMP-288 was administered 16 hours after TF10. At 3 hours postadministration of radiolabeled peptide, imaging showed intense uptake within the tumors and no evidence of accretion in any normal tissue. No targeting was observed in animals given only the ¹¹¹In-peptide. Tumor uptake of the TF10-pretargeted ¹¹¹In-IMP-288 was 24.3 ± 1.7% ID/g, whereas for ¹¹¹In-IMP-288 alone it was only 0.12 ± 0.002% ID/g at 16 hours. Tumor/blood ratios were significantly greater for the pretargeting group (1,000:1 at 3 hours) compared with ¹¹¹In-PAM4-IgG (5:1 at 24 hours; P < 0.0003). Radiation dose estimates suggested that TF10/⁹⁰Y-peptide pretargeting would provide a greater antitumor effect than ⁹⁰Y-PAM4-IgG. Thus, the results suggest that TF10 pretargeting may provide improved imaging for early detection, diagnosis, and treatment of pancreatic cancer as compared with directly radiolabeled PAM4-IgG. [Cancer Res 2008;68(12):4819–26]

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