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: Weibo Cai, Yun Wu, Kai Chen, Qizhen Cao, David A Tice, Xiaoyuan Chen
• Journal: Cancer research (Cancer Res) Vol. 66 Issue 19 Pg. 9673-81 (Oct 01 2006) ISSN: 1538-7445 [Electronic] United States
• PMID: 17018625 (Publication Type: Journal Article, Research Support, N.I.H., Extramural, Research Support, Non-U.S. Gov't, Research Support, U.S. Gov't, Non-P.H.S.)

Chemical References

• 64Cu-DOTA-abergrin
• Angiogenesis Inhibitors
• Antibodies, Monoclonal
• Antibodies, Monoclonal, Humanized
• Chelating Agents
• Copper Radioisotopes
• Heterocyclic Compounds, 1-Ring
• Immunoconjugates
• Integrin alphaVbeta3
• Neoplasm Proteins
• Organometallic Compounds
• 1,4,7,10-tetraazacyclododecane- 1,4,7,10-tetraacetic acid
• etaracizumab

Topics

• Adenocarcinoma (chemistry, diagnostic imaging, pathology)
• Angiogenesis Inhibitors (analysis, immunology, pharmacokinetics)
• Animals
• Antibodies, Monoclonal (analysis, immunology, pharmacokinetics)
• Antibodies, Monoclonal, Humanized
• Breast Neoplasms (chemistry, diagnostic imaging, pathology)
• Cell Line, Tumor (diagnostic imaging, transplantation)
• Chelating Agents (administration & dosage, pharmacokinetics)
• Copper Radioisotopes (administration & dosage, analysis, pharmacokinetics)
• Female
• Glioblastoma (chemistry, diagnostic imaging, pathology)
• Heterocyclic Compounds, 1-Ring (administration & dosage, pharmacokinetics)
• Humans
• Immunoconjugates (analysis, immunology, pharmacokinetics)
• Integrin alphaVbeta3 (analysis, immunology)
• Male
• Mice
• Mice, Nude
• Neoplasm Proteins (analysis, immunology)
• Organometallic Compounds (analysis, immunology, pharmacokinetics)
• Positron-Emission Tomography
• Prostatic Neoplasms (chemistry, diagnostic imaging)
• Radiography
• Radioimmunodetection
• Radiometry
• Tissue Distribution