In vitro and in vivo characterization of 64Cu-labeled Abegrin, a humanized monoclonal antibody against integrin alpha v beta 3

Cancer Res. 2006 Oct 1;66(19):9673-81. doi: 10.1158/0008-5472.CAN-06-1480.

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.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't
  • Research Support, U.S. Gov't, Non-P.H.S.

MeSH terms

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

Substances

  • 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