Comparison of Pretargeted and Conventional CC49 Radioimmunotherapy Using 149Pm, 166Ho, and 177Lu

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• 作者：Huma Mohsin ; Fang Jia ; Jeffrey N. Bryan ; Geethapriya Sivaguru ; Cathy S. Cutler ; Alan R. Ketring ; William H. Miller ; Jim Sim贸n ; R. Keith Frank ; Louis J. Theodore ; Don B. Axworthy ; Silvia S. Jurisson ; Michael R. Lewis
• 刊名：Bioconjugate Chemistry
• 出版年：2011
• 出版时间：December 21, 2011
• 年：2011
• 卷：22
• 期：12
• 页码：2444-2452
• 全文大小：385K
• 年卷期：v.22,no.12(December 21, 2011)
• ISSN：1520-4812

文摘

The therapeutic efficacies of radiolabeled biotin, pretargeted by monoclonal antibody (mAb)鈥搒treptavidin fusion protein CC49 scFvSA, were compared to those of radiolabeled mAb CC49, using the three radiolanthanides in an animal model of human colon cancer. The purpose of the present study was to compare antibody pretargeting to conventional radioimmunotherapy using ¹⁴⁹Pm, ¹⁶⁶Ho, or ¹⁷⁷Lu. Nude mice bearing LS174T colon tumors were injected sequentially with CC49 scFvSA, the blood clearing agent biotin-GalNAc₁₆, and ¹⁴⁹Pm-, ¹⁶⁶Ho-, or ¹⁷⁷Lu-DOTA-biotin. Tumor-bearing mice were alternatively administered ¹⁴⁹Pm-, ¹⁶⁶Ho-, or ¹⁷⁷Lu-MeO-DOTA-CC49. Therapy with pretargeted ¹⁴⁹Pm-,¹⁶⁶Ho-, and ¹⁷⁷Lu-DOTA-biotin increased the median time of progression to a 1 g tumor to 50, 41, and 50 days post-treatment, respectively. Therapy with ¹⁴⁹Pm-,¹⁶⁶Ho-, and ¹⁷⁷Lu-MeO-DOTA-CC49 increased the median time to progression to 53, 24, and 67 days post-treatment, respectively. In contrast, saline controls showed a median time to progression of 13 days postinjection. Treatment with pretargeted ¹⁴⁹Pm-, ¹⁶⁶Ho-, and ¹⁷⁷Lu-biotin or ¹⁴⁹Pm-, ¹⁶⁶Ho-, and ¹⁷⁷Lu-CC49 increased tumor doubling time to 18鈥?6 days, compared to 3 days for saline controls. Among treated mice, 23% survived >84 days post-therapy, and 11% survived 6 months, but controls survived <29 days. Long-term survivors showed tumor growth inhibition or partial regression, extensive necrosis in residual masses, and no evidence of nontarget tissue toxicity at necropsy. Both pretargeted and conventional RIT demonstrated considerable efficacy in an extremely aggressive animal model of cancer. Our results identified ¹⁷⁷Lu as an optimal radiolanthanide for future evaluation of these agents in toxicity and multiple-dose therapy studies.