title: In vitro and in vivo characterization of 64Cu-labeled Abegrin, a humanized monoclonal antibody against integrin alpha v beta 3.
abstract: Abegrin (MEDI-522 or Vitaxin), a humanized monoclonal antibody against human integrin alpha(v)beta(3), is in clinical trials for cancer therapy. In vivo imaging using Abegrin-based probes is needed for better treatment monitoring and dose optimization. Here, we conjugated Abegrin with macrocyclic chelating agent 1,4,7,10-tetra-azacylododecane N,N',N'',N'''-tetraacetic (DOTA) at five different DOTA/Abegrin ratios. The conjugates were labeled with (64)Cu (half-life = 12.7 hours) and tested in three human (U87MG, MDA-MB-435, and PC-3) and one mouse (GL-26) tumor models. The in vitro and in vivo effects of these (64)Cu-DOTA-Abegrin conjugates were evaluated. The number of DOTA per Abegrin varied from 1.65 +/- 0.32 to 38.53 +/- 5.71 and the radiolabeling yield varied from 5.20 +/- 3.16% to 88.12 +/- 6.98% (based on 2 mCi (64)Cu per 50 microg DOTA-Abegrin conjugate). No significant difference in radioimmunoreactivity was found among these conjugates (between 59.78 +/- 1.33 % and 71.13 +/- 2.58 %). Micro-positron emission tomography studies revealed that (64)Cu-DOTA-Abegrin (1,000:1) had the highest tumor activity accumulation (49.41 +/- 4.54% injected dose/g at 71-hour postinjection for U87MG tumor). The receptor specificity of (64)Cu-DOTA-Abegrin was confirmed by effective blocking of MDA-MB-435 tumor uptake with coadministration of nonradioactive Abegrin. (64)Cu-DOTA-IgG exhibited background level tumor uptake at all time points examined. Integrin alpha(v)beta(3)-specific tumor imaging using (64)Cu-DOTA-Abegrin may be translated into the clinic to characterize the pharmacokinetics, tumor targeting efficacy, dose optimization, and dose interval of Abegrin and/or Abegrin conjugates. Chemotherapeutics or radiotherapeutics using Abegrin as the delivering vehicle may also be effective in treating integrin alpha(v)beta(3)-positive tumors.
authors.affiliation: The Molecular Imaging Program at Stanford, Department of Radiology and Bio-X Program, Stanford University School of Medicine, Stanford, CA 94305-5484, USA.
authors.forename: Weibo
authors.initials: W
authors.lastname: Cai
authors.forename: Yun
authors.initials: Y
authors.lastname: Wu
authors.forename: Kai
authors.initials: K
authors.lastname: Chen
authors.forename: Qizhen
authors.initials: Q
authors.lastname: Cao
authors.forename: David A
authors.initials: DA
authors.lastname: Tice
authors.forename: Xiaoyuan
authors.initials: X
authors.lastname: Chen
mesh_terms: D000230:Adenocarcinoma / Q000737:chemistry / Q000000981:diagnostic imaging / Q000473:pathology; D020533:Angiogenesis Inhibitors / Q000032:analysis / Q000276:immunology / Q000493:pharmacokinetics*; D000818:Animals; D000911:Antibodies, Monoclonal / Q000032:analysis / Q000276:immunology / Q000493:pharmacokinetics*; D061067:Antibodies, Monoclonal, Humanized; D001943:Breast Neoplasms / Q000737:chemistry / Q000000981:diagnostic imaging / Q000473:pathology; D045744:Cell Line, Tumor / Q000000981:diagnostic imaging / Q000637:transplantation; D002614:Chelating Agents / Q000008:administration & dosage / Q000493:pharmacokinetics; D003301:Copper Radioisotopes / Q000008:administration & dosage / Q000032:analysis / Q000493:pharmacokinetics*; D005260:Female; D005909:Glioblastoma / Q000737:chemistry / Q000000981:diagnostic imaging / Q000473:pathology; D006573:Heterocyclic Compounds, 1-Ring / Q000008:administration & dosage / Q000493:pharmacokinetics; D006801:Humans; D018796:Immunoconjugates / Q000032:analysis / Q000276:immunology / Q000493:pharmacokinetics*; D039302:Integrin alphaVbeta3 / Q000032:analysis / Q000276:immunology*; D008297:Male; D051379:Mice; D008819:Mice, Nude; D009363:Neoplasm Proteins / Q000032:analysis / Q000276:immunology*; D009942:Organometallic Compounds / Q000032:analysis / Q000276:immunology / Q000493:pharmacokinetics*; D049268:Positron-Emission Tomography; D011471:Prostatic Neoplasms / Q000737:chemistry / Q000000981:diagnostic imaging; D011859:Radiography; D016719:Radioimmunodetection; D011874:Radiometry; D014018:Tissue Distribution
chemical_list: C524058:64Cu-DOTA-abergrin; D020533:Angiogenesis Inhibitors; D000911:Antibodies, Monoclonal; D061067:Antibodies, Monoclonal, Humanized; D002614:Chelating Agents; D003301:Copper Radioisotopes; D006573:Heterocyclic Compounds, 1-Ring; D018796:Immunoconjugates; D039302:Integrin alphaVbeta3; D009363:Neoplasm Proteins; D009942:Organometallic Compounds; C071349:1,4,7,10-tetraazacyclododecane- 1,4,7,10-tetraacetic acid; C112567:etaracizumab