Data from A Novel Bispecific, Trivalent Antibody Construct for Targeting Pancreatic Carcinoma

Abstract

<div>Abstract<p>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. <sup>125</sup>I-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, <sup>111</sup>In-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 <sup>111</sup>In-peptide. Tumor uptake of the TF10-pretargeted <sup>111</sup>In-IMP-288 was 24.3 ± 1.7% ID/g, whereas for <sup>111</sup>In-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 <sup>111</sup>In-PAM4-IgG (∼5:1 at 24 hours; <i>P</i> < 0.0003). Radiation dose estimates suggested that TF10/<sup>90</sup>Y-peptide pretargeting would provide a greater antitumor effect than <sup>90</sup>Y-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]</p></div>