title: In vivo comparison of macrocyclic and acyclic ligands for radiolabeling of monoclonal antibodies with 177Lu for radioimmunotherapeutic applications.
abstract: The studies reported herein present the first in vitro and in vivo comparison of radioimmunoconjugates (RIC) radiolabeled with 177Lu using the acyclic CHX-A"-DTPA ligand and the macrocyclic ligands, C-DOTA and PA-DOTA. The in vivo studies include pharmacokinetics and biodistribution of the formed 177Lu-labeled immunoconjugates in a tumor bearing murine model with engineered monoclonal antibody HuCC49DeltaCH2. The in vitro analysis indicated that the CHX-A" RIC was superior with respect to immunoreactivity, radiolabeling with 177Lu, and specific activity. The in vivo pharmacokinetic data by itself indicated that the Lu(III)-PA-DOTA complex may not be as stable as Lu(III) complexes with CHX-A" or C-DOTA. All three RICs demonstrated tumor targeting of human colon carcinoma xenografts in athymic mice. In these biodistribution studies, there appears to be no overall pattern or trend of one RIC over the other two. Based on these in vitro and in vivo studies, the CHX-A" DTPA ligand should be considered a suitable bifunctional chelate for the radiolabeling of monoclonal antibodies with 177Lu for radioimmunotherapy applications.
authors.affiliation: Chemistry Section, Radiation Oncology Branch, National Cancer Institute, Bethesda, Maryland 20892, USA.
authors.forename: Diane E
authors.initials: DE
authors.lastname: Milenic
authors.forename: Kayhan
authors.initials: K
authors.lastname: Garmestani
authors.forename: Lara L
authors.initials: LL
authors.lastname: Chappell
authors.forename: Ekaterina
authors.initials: E
authors.lastname: Dadachova
authors.forename: Alexander
authors.initials: A
authors.lastname: Yordanov
authors.forename: Dangshe
authors.initials: D
authors.lastname: Ma
authors.forename: Jeffrey
authors.initials: J
authors.lastname: Schlom
authors.forename: Martin W
authors.initials: MW
authors.lastname: Brechbiel
mesh_terms: D000230:Adenocarcinoma / Q000378:metabolism* / Q000532:radiotherapy; D000814:Aniline Compounds / Q000493:pharmacokinetics; D000818:Animals; D000911:Antibodies, Monoclonal / Q000493:pharmacokinetics*; D003110:Colonic Neoplasms / Q000378:metabolism* / Q000532:radiotherapy; D005260:Female; D006571:Heterocyclic Compounds / Q000493:pharmacokinetics; D006573:Heterocyclic Compounds, 1-Ring / Q000493:pharmacokinetics*; D006801:Humans; D018796:Immunoconjugates / Q000493:pharmacokinetics; D017879:Isothiocyanates / Q000493:pharmacokinetics*; D008187:Lutetium / Q000493:pharmacokinetics*; D051379:Mice; D008819:Mice, Nude; D004369:Pentetic Acid / Q000031:analogs & derivatives* / Q000493:pharmacokinetics*; D016499:Radioimmunotherapy; D019275:Radiopharmaceuticals / Q000493:pharmacokinetics; D012680:Sensitivity and Specificity; D014018:Tissue Distribution; D014915:Whole-Body Counting; D023041:Xenograft Model Antitumor Assays
chemical_list: D000814:Aniline Compounds; D000911:Antibodies, Monoclonal; D006571:Heterocyclic Compounds; D006573:Heterocyclic Compounds, 1-Ring; D018796:Immunoconjugates; D017879:Isothiocyanates; D019275:Radiopharmaceuticals; C085738:4-aminophenylethyl-1,4,7,10-tetraazacyclodecane-N,N',N'',N'''-tetraacetic acid; C085678:N-(2-amino-3-(4-isothiocyanatophenyl)propyl)cyclohexane-1,2-diamine-N,N',N',N'',N''-pentaacetic acid; C071349:1,4,7,10-tetraazacyclododecane- 1,4,7,10-tetraacetic acid; D008187:Lutetium; D004369:Pentetic Acid