In vitro and in vivo characterization of 64Cu-labeled Abegrin™ a humanized monoclonal antibody against integrin αvβ3

Abegrin (TM) (MEDI-522 or Vitaxin (TM)), a humanized monoclonal antibody against human integrin alpha(v)beta(3) is in clinical trials for cancer therapy. In vivo imaging using Abegrin (TM)-based probes is needed for better treatment monitoring and dose optimization. Here, we conjugated Abegrin (TM) with macrocyclic chelating agent 1,4,7,10-tetra-azacylododecane N,N',N'',N''-tetraacetic (DOTA) at five different DOTA/Abegrin (TM) ratios. The conjugates were labeled with (CU)-C-64 (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 Cu-64-DOTA-Abegirin (TM) conjugates were evaluated. The number of DOTA per Abegrin (TM) 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 (CU)-C-64 per 50 mu g DOTA-Abegrin (TM) 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 Cu-64-DOTA-Abegrin (TM) (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 Cu-64-DOTA-Abegrin was confirmed by effective blocking of MDA-MB-435 tumor uptake with coadministration of nonradioactive Abegrin. Cu-64-DOTA-IgG exhibited background level tumor uptake at all time points examined. Integrin alpha(v)beta(3)-specific tumor imaging using Cu-64-DOTA-Abegrin (TM) may be translated into the clinic to characterize the pharmacokinetics, tumor targeting efficacy, dose optimization, and dose interval of Abegrin (TM) and/or Abegrin conjugates. Chemotherapeutics or radiotherapeutics using Abegrin (TM) as the delivering vehicle may also be effective in treating integrin alpha(v)beta(3)-positive tumors.