In vitro and In vivo Characterization of 64Cu-Labeled AbegrinTM, a Humanized Monoclonal Antibody against Integrin αvβ3

Abstract

AbegrinTM (MEDI-522 or VitaxinTM), a humanized monoclonal antibody against human integrin αvβ3, is in clinical trials for cancer therapy. In vivo imaging using AbegrinTM-based probes is needed for better treatment monitoring and dose optimization. Here, we conjugated AbegrinTM with macrocyclic chelating agent 1,4,7,10-tetra-azacylododecane N,N′,N″,N‴-tetraacetic (DOTA) at five different DOTA/AbegrinTM ratios. The conjugates were labeled with 64Cu (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 64Cu-DOTA-AbegrinTM conjugates were evaluated. The number of DOTA per AbegrinTM 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 64Cu per 50 μg DOTA-AbegrinTM 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 64Cu-DOTA-AbegrinTM (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 64Cu-DOTA-Abegrin was confirmed by effective blocking of MDA-MB-435 tumor uptake with coadministration of nonradioactive Abegrin. 64Cu-DOTA-IgG exhibited background level tumor uptake at all time points examined. Integrin αvβ3-specific tumor imaging using 64Cu-DOTA-AbegrinTM may be translated into the clinic to characterize the pharmacokinetics, tumor targeting efficacy, dose optimization, and dose interval of AbegrinTM and/or Abegrin conjugates. Chemotherapeutics or radiotherapeutics using AbegrinTM as the delivering vehicle may also be effective in treating integrin αvβ3-positive tumors. (Cancer Res 2006; 66(19): 9673-81)