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In vitro and In vivo Characterization of ⁶⁴Cu-Labeled Abegrin^TM, a Humanized Monoclonal Antibody against Integrin _vß₃

¹ The Molecular Imaging Program at Stanford, Department of Radiology and Bio-X Program, Stanford University School of Medicine, Stanford, California and ² MedImmune, Inc., Gaithersburg, Maryland

Requests for reprints: Xiaoyuan Chen, The Molecular Imaging Program at Stanford, Department of Radiology and Bio-X Program, Stanford University School of Medicine, 1201 Welch Road, P095, Stanford, CA 94305-5484. Phone: 650-725-0950; Fax: 650-736-7925; E-mail: shawchen{at}stanford.edu.

Abegrin^TM (MEDI-522 or Vitaxin^TM), a humanized monoclonal antibody against human integrin _vß₃, 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 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-Abegrin^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 ⁶⁴Cu per 50 µg 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 ⁶⁴Cu-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 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 _vß₃-specific tumor imaging using ⁶⁴Cu-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 _vß₃-positive tumors. (Cancer Res 2006; 66(19): 9673-81)

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