Radioimmunotherapy of breast cancer xenografts with monoclonal antibody ICR12 against c-erbB2 p185: comparison of iodogen and N-succinimidyl 4-methyl-3-(tri-n-butylstannyl)benzoate radioiodination methods

Abstract

C-erbB2 p185 is a proto-oncogene product expressed in 25-30% of human invasive breast cancers that is associated with poor prognosis and resistance to endocrine therapy and chemotherapy. It is minimally expressed in normal adult tissues (M. F. Press et al., Oncogene, 5: 953-962, 1990). For this reason, it is an attractive target for radioimmunotherapy and other antibody-directed therapies. ICR12 is a rat IgG2a monoclonal antibody directed against a protein epitope of the external domain of the c-erbB2 p185. We performed experiments to optimize the direct iodination of ICR12 with 131I using the IodoGen method, and we found impairment of immunoreactive fraction with increasing specific activity. N-Succinimidyl 4-methyl-3-(tri-n-butylstannyl)benzoate (MATE) is a tin ester that can be radioiodinated easily and then coupled to the epsilon-amino group of lysine residues. This method has been shown to have improved uptake in tumors compared with antibody labeled by direct iodination (P. K. Garg et al., Nucl. Med. Biol., 20: 379-387, 1993). ICR12 could be labeled up to 16 mCi/mg by this technique without loss of immunoreactive fraction. Whole-body retention of MATE-labeled ICR12 was less than IodoGen (P < 0.0001). Radioimmunotherapy experiments in athymic mice bearing established MDA MB 361 human breast cancer xenografts showed growth inhibition for > 24 days at a dose of 600 microCi/mouse (P < 0.0001) when labeled by the IodoGen technique, and 12 days using the MATE method (P < 0.0001).