title: SIB-DOTA: a trifunctional prosthetic group potentially amenable for multi-modal labeling that enhances tumor uptake of internalizing monoclonal antibodies.
abstract: A major drawback of internalizing monoclonal antibodies (mAbs) radioiodinated with direct electrophilic approaches is that tumor retention of radioactivity is compromised by the rapid washout of iodo-tyrosine, the primary labeled catabolite for mAbs labeled via this strategy. In our continuing efforts to develop more versatile residualizing labels that could overcome this problem, we have designed SIB-DOTA, a prosthetic labeling template that combines the features of the prototypical, dehalogenation-resistant N-succinimidyl 3-iodobenzoate (SIB) with DOTA, a useful macrocyclic chelator for labeling with radiometals. Herein we describe the synthesis of the unlabeled standard of this prosthetic moiety, its protected tin precursor, and radioiodinated SIB-DOTA. An anti-EGFRvIII-reactive mAb, L8A4 was radiolabeled with [(131)I]SIB-DOTA in 27.1±6.2% (n=2) conjugation yields and its targeting properties to the same mAb labeled with [(125)I]SGMIB both in vitro and in vivo using U87MG·ΔEGFR cells and xenografts were compared. In vitro paired-label internalization assays showed that the intracellular radioactivity from [(131)I]SIB-DOTA-L8A4 was 21.4±0.5% and 26.2±1.1% of initially bound radioactivity at 16 and 24h, respectively. In comparison, these values for [(125)I]SGMIB-L8A4 were 16.7±0.5% and 14.9±1.1%. Similarly, the SIB-DOTA prosthetic group provided better tumor targeting in vivo than SGMIB over 8 d period. These results suggest that SIB-DOTA warrants further evaluation as a residualizing agent for labeling internalizing mAbs including those targeted to EGFRvIII.
authors.affiliation: Box 3808, Radiology, Duke University Medical Center, Durham, NC 27710, USA. ganesan.v@duke.edu
authors.forename: G
authors.initials: G
authors.lastname: Vaidyanathan
authors.forename: B J
authors.initials: BJ
authors.lastname: White
authors.forename: D J
authors.initials: DJ
authors.lastname: Affleck
authors.forename: X G
authors.initials: XG
authors.lastname: Zhao
authors.forename: P C
authors.initials: PC
authors.lastname: Welsh
authors.forename: D
authors.initials: D
authors.lastname: McDougald
authors.forename: J
authors.initials: J
authors.lastname: Choi
authors.forename: M R
authors.initials: MR
authors.lastname: Zalutsky
mesh_terms: D000818:Animals; D000911:Antibodies, Monoclonal / Q000737:chemistry* / Q000276:immunology / Q000493:pharmacokinetics*; D045744:Cell Line, Tumor; D066246:ErbB Receptors / Q000276:immunology; D005909:Glioblastoma / Q000276:immunology / Q000378:metabolism; D006573:Heterocyclic Compounds, 1-Ring / Q000138:chemical synthesis / Q000737:chemistry* / Q000493:pharmacokinetics; D006801:Humans; D000922:Immunotoxins / Q000737:chemistry* / Q000493:pharmacokinetics*; D007457:Iodine Radioisotopes / Q000737:chemistry / Q000493:pharmacokinetics; D007463:Iodobenzoates / Q000138:chemical synthesis / Q000737:chemistry* / Q000493:pharmacokinetics; D007553:Isotope Labeling / Q000379:methods; D051379:Mice; D008807:Mice, Inbred BALB C; D009942:Organometallic Compounds / Q000737:chemistry; D019275:Radiopharmaceuticals / Q000138:chemical synthesis* / Q000737:chemistry / Q000276:immunology / Q000493:pharmacokinetics; D014001:Tin / Q000737:chemistry; D014018:Tissue Distribution
chemical_list: D000911:Antibodies, Monoclonal; D006573:Heterocyclic Compounds, 1-Ring; D000922:Immunotoxins; D007457:Iodine Radioisotopes; D007463:Iodobenzoates; D009942:Organometallic Compounds; D019275:Radiopharmaceuticals; C410723:epidermal growth factor receptor VIII; C071349:1,4,7,10-tetraazacyclododecane- 1,4,7,10-tetraacetic acid; D014001:Tin; C062337:N-succinimidyl 3-iodobenzoate; D066246:ErbB Receptors