title: Comparison of pretargeted and conventional CC49 radioimmunotherapy using 149Pm, 166Ho, and 177Lu.
abstract: The therapeutic efficacies of radiolabeled biotin, pretargeted by monoclonal antibody (mAb)-streptavidin 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 (149)Pm, (166)Ho, or (177)Lu. Nude mice bearing LS174T colon tumors were injected sequentially with CC49 scFvSA, the blood clearing agent biotin-GalNAc(16), and (149)Pm-, (166)Ho-, or (177)Lu-DOTA-biotin. Tumor-bearing mice were alternatively administered (149)Pm-, (166)Ho-, or (177)Lu-MeO-DOTA-CC49. Therapy with pretargeted (149)Pm-,(166)Ho-, and (177)Lu-DOTA-biotin increased the median time of progression to a 1 g tumor to 50, 41, and 50 days post-treatment, respectively. Therapy with (149)Pm-,(166)Ho-, and (177)Lu-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 (149)Pm-, (166)Ho-, and (177)Lu-biotin or (149)Pm-, (166)Ho-, and (177)Lu-CC49 increased tumor doubling time to 18-36 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 (177)Lu as an optimal radiolanthanide for future evaluation of these agents in toxicity and multiple-dose therapy studies.
authors: Department of Chemistry, University of Missouri-Columbia, Columbia, Missouri, United States.
authors: Huma
authors: H
authors: Mohsin
authors: Fang
authors: F
authors: Jia
authors: Jeffrey N
authors: JN
authors: Bryan
authors: Geethapriya
authors: G
authors: Sivaguru
authors: Cathy S
authors: CS
authors: Cutler
authors: Alan R
authors: AR
authors: Ketring
authors: William H
authors: WH
authors: Miller
authors: Jim
authors: J
authors: Simón
authors: R Keith
authors: RK
authors: Frank
authors: Louis J
authors: LJ
authors: Theodore
authors: Don B
authors: DB
authors: Axworthy
authors: Silvia S
authors: SS
authors: Jurisson
authors: Michael R
authors: MR
authors: Lewis
mesh_terms: D000818:Animals; D000912:Antibodies, Neoplasm / Q000627:therapeutic use*; D000970:Antineoplastic Agents / Q000627:therapeutic use*; D001710:Biotin / Q000031:analogs & derivatives / Q000737:chemistry; D045744:Cell Line, Tumor; D003110:Colonic Neoplasms / Q000473:pathology / Q000532:radiotherapy*; D016503:Drug Delivery Systems; D005260:Female; D006801:Humans; D028581:Lanthanoid Series Elements / Q000627:therapeutic use*; D051379:Mice; D008819:Mice, Nude; D009942:Organometallic Compounds / Q000737:chemistry; D016499:Radioimmunotherapy / Q000379:methods*; D019275:Radiopharmaceuticals / Q000627:therapeutic use*; D011993:Recombinant Fusion Proteins / Q000627:therapeutic use; D019809:Streptavidin / Q000627:therapeutic use*
chemical_list: D000912:Antibodies, Neoplasm; D000970:Antineoplastic Agents; C091202:B72.3 antibody; C405616:DOTA-biotin; D028581:Lanthanoid Series Elements; D009942:Organometallic Compounds; D019275:Radiopharmaceuticals; D011993:Recombinant Fusion Proteins; D001710:Biotin; D019809:Streptavidin