title: Enhanced tumor retention of a radiohalogen label for site-specific modification of antibodies.
abstract: A known limitation of iodine radionuclides for labeling and biological tracking of receptor targeted proteins is the tendency of iodotyrosine to rapidly diffuse from cells following endocytosis and lysosomal degradation. In contrast, radiometal-chelate complexes such as indium-111-1,4,7,10-tetraazacyclododecane-1,4,7,10-tetraacetic acid (In-111-DOTA) accumulate within target cells due to the residualizing properties of the polar, charged metal-chelate-amino acid adduct. Iodine radionuclides boast a diversity of nuclear properties and chemical means for incorporation, prompting efforts to covalently link radioiodine with residualizing molecules. Herein, we describe the Ugi-assisted synthesis of [I-125]HIP-DOTA, a 4-hydroxy-3-iodophenyl (HIP) derivative of DOTA, and demonstration of its residualizing properties in a murine xenograft model. Overall, this study displays the power of multicomponent synthesis to yield a versatile radioactive probe for antibodies across multiple therapeutic areas with potential applications in both preclinical biodistribution studies and clinical radioimmunotherapies.
authors.affiliation: Genentech Research and Early Development, 1 DNA Way MS 463A , South San Francisco 94080, United States.
authors.forename: C Andrew
authors.initials: CA
authors.lastname: Boswell
authors.forename: Jan
authors.initials: J
authors.lastname: Marik
authors.forename: Michael J
authors.initials: MJ
authors.lastname: Elowson
authors.forename: Noe A
authors.initials: NA
authors.lastname: Reyes
authors.forename: Sheila
authors.initials: S
authors.lastname: Ulufatu
authors.forename: Daniela
authors.initials: D
authors.lastname: Bumbaca
authors.forename: Victor
authors.initials: V
authors.lastname: Yip
authors.forename: Eduardo E
authors.initials: EE
authors.lastname: Mundo
authors.forename: Nicholas
authors.initials: N
authors.lastname: Majidy
authors.forename: Marjie
authors.initials: M
authors.lastname: Van Hoy
authors.forename: Saritha N
authors.initials: SN
authors.lastname: Goriparthi
authors.forename: Anthony
authors.initials: A
authors.lastname: Trias
authors.forename: Herman S
authors.initials: HS
authors.lastname: Gill
authors.forename: Simon P
authors.initials: SP
authors.lastname: Williams
authors.forename: Jagath R
authors.initials: JR
authors.lastname: Junutula
authors.forename: Paul J
authors.initials: PJ
authors.lastname: Fielder
authors.forename: Leslie A
authors.initials: LA
authors.lastname: Khawli
mesh_terms: D000818:Animals; D058846:Antibodies, Monoclonal, Murine-Derived / Q000737:chemistry / Q000378:metabolism* / Q000627:therapeutic use; D056831:Coordination Complexes / Q000378:metabolism; D004151:Dipeptides / Q000138:chemical synthesis* / Q000378:metabolism; D006573:Heterocyclic Compounds, 1-Ring / Q000138:chemical synthesis* / Q000378:metabolism; D018796:Immunoconjugates / Q000737:chemistry* / Q000378:metabolism; D007205:Indium Radioisotopes; D051379:Mice; D016499:Radioimmunotherapy; D013388:Succinimides / Q000138:chemical synthesis* / Q000378:metabolism; D023041:Xenograft Model Antitumor Assays
chemical_list: D058846:Antibodies, Monoclonal, Murine-Derived; D056831:Coordination Complexes; D004151:Dipeptides; D006573:Heterocyclic Compounds, 1-Ring; D018796:Immunoconjugates; D007205:Indium Radioisotopes; D013388:Succinimides; C586738:indium-111-1,4,7,10-tetraazacyclododecane-1,4,7,10-tetraacetic acid