title: Comparison of 1,4,7,10-tetraazacyclododecane-N,N',N'',N'''-tetraacetic acid (DOTA)-peptide-ChL6, a novel immunoconjugate with catabolizable linker, to 2-iminothiolane-2-[p-(bromoacetamido)benzyl]-DOTA-ChL6 in breast cancer xenografts.
abstract: Radioimmunotherapy using 131I-ChL6 antibody has shown promise in patients with breast cancer. To enhance this potential, a novel ChL6 immunoconjugate that is catabolizable and tightly binds 90Y and (111)In was developed. The immunoconjugate, 1,4,7,10-tetraazacyclododecane-N,N',N'',N'''-tetraacetic acid (DOTA)-peptide-ChL6, consists of the macrocyclic chelator DOTA linked to ChL6 by a peptide that is preferentially catabolized in the liver. The pharmacokinetic and dosimetric properties of the radioimmunoconjugates (RICs) (111)In- and 90Y-DOTA-peptide-ChL6 and (111)In- and 90Y-2-iminothiolane (2-IT)-2-[p-(bromoacetamido)benzyl]-DOTA-ChL6 were compared in athymic mice bearing HBT3477 human breast cancer xenografts. Each of the RICs was stable in vivo and concentrated well in the xenografts. Liver concentration, cumulative radioactivity (activity over time), and radiation dose of the DOTA-peptide-ChL6 RICs were one-third to one-half of those of the corresponding 2-IT-2-[p(bromoacetamido)benzyl]-DOTA-ChL6 RICs. Indium-111 RICs were imperfect tracers for corresponding 90Y RICs, although their pharmacokinetics and radiation dosimetries were similar. The results of this study were consistent with previously published in vitro data, which indicated that the peptide linker of DOTA-peptide-ChL6 was catabolized by cathepsin B. The cumulative activities and radiation doses to the liver of DOTA-peptide-ChL6 RICs were one-half of those of corresponding RICs with the 2-IT linker. Preliminary data from pilot studies in patients with breast cancer are in accord with these observations. These novel DOTA-peptide RICs seem to have excellent clinical potential for radioimmunotherapy associated with marrow transplantation, for which liver radiation is likely to be dose limiting for 90Y.
authors.affiliation: Department of Internal Medicine, University of California Davis, School of Medicine, Sacramento 95816, USA.
authors.forename: G L
authors.initials: GL
authors.lastname: DeNardo
authors.forename: L A
authors.initials: LA
authors.lastname: Kroger
authors.forename: C F
authors.initials: CF
authors.lastname: Meares
authors.forename: C M
authors.initials: CM
authors.lastname: Richman
authors.forename: Q
authors.initials: Q
authors.lastname: Salako
authors.forename: S
authors.initials: S
authors.lastname: Shen
authors.forename: K R
authors.initials: KR
authors.lastname: Lamborn
authors.forename: J J
authors.initials: JJ
authors.lastname: Peterson
authors.forename: L A
authors.initials: LA
authors.lastname: Miers
authors.forename: G R
authors.initials: GR
authors.lastname: Zhong
authors.forename: S J
authors.initials: SJ
authors.lastname: DeNardo
mesh_terms: D000818:Animals; D000911:Antibodies, Monoclonal / Q000627:therapeutic use*; D002614:Chelating Agents / Q000493:pharmacokinetics*; D005260:Female; D006801:Humans; D018796:Immunoconjugates / Q000493:pharmacokinetics*; D007205:Indium Radioisotopes / Q000627:therapeutic use; D008325:Mammary Neoplasms, Experimental / Q000532:radiotherapy*; D051379:Mice; D009368:Neoplasm Transplantation; D011829:Radiation Dosage; D016499:Radioimmunotherapy; D014183:Transplantation, Heterologous; D015021:Yttrium Radioisotopes / Q000627:therapeutic use
chemical_list: D000911:Antibodies, Monoclonal; C106337:ChL6 monoclonal antibody; D002614:Chelating Agents; D018796:Immunoconjugates; D007205:Indium Radioisotopes; D015021:Yttrium Radioisotopes