A comparison of HER2 tumor accumulations of Ga-67 labeled anti-HER2 antibody with chemically and site-specifically conjugated bifunctional chelators
Abstract Background Monoclonal antibodies (mAb) developed to target specific cancers have achieved considerable success to-date. To further enhance therapeutic efficacy monoclonal antibodies may be conjugated with a cytotoxic drug or radioisotope. We present the development of new method based on site-specific conjugation (SSC) for targeting HER2. The study design involves a comparison of the accumulation of Ga-67 labeled anti-HER2 antibodies with SSC versus conventional chemical conjugation in HER2-positive tumors. Anti-HER2 antibodies were chemically conjugated (Chem) with the bifunctional chelator deferoxamine (Chem-mAb). The resulting chemical conjugate was radiolabeled with Ga-67 yielding Ga-67-Chem -mAb. The SSC anti-HER2 antibodies enzymatically conjugated with deferoxamine using transglutaminase (SSC-mAb) and radiolabeled with Ga-67 yielding Ga-67-SSC-mAb. In vitro, the binding activity of HER2 to both conjugated antibodies was measured using surface Plasmon resonance. In vivo, a xenograft mouse model consisting of transplanted CHO/HER2 were divided into two groups, the Chem and the SSC group. Planar images were acquired over three days after each mAb injection, respectively. Pharmacokinetic analysis was used to compare the Chem group to the SSC group, for Ga-67 accumulation. Result The SSC and Chem groups were found to have similar HER2 binding capacity, however the tumor accumulation ratio gradually increased in the SSC group. The pharmacokinetic studies also found that radiolabeled mAb accumulation was significantly higher in the SSC group than the Chem group in not only the tumors, but also in blood and in other organs. Conclusion The new site-specific conjugation may improve targeted antigen-specific cancer radioimmunotherapy and may, due to higher retention, require a lower dose.