Owing to the poor transport of monoclonal antibodies across either capillary or cell membrane barriers, drug delivery strategies are needed to target monoclonal antibodies to intracellular sites where proteins function. One antibody drug delivery strategy is cationization, wherein the isoelectric point (pl) is raised by conversion of surface carboxyl groups to extended primary amino groups. The present studies describe the cationization of a murine monoclonal antibody (D146) prepared against a synthetic peptide encoding the Asp13 point mutation of the ras protooncogenic p21 protein. The pl of the D146 monoclonal antibody was raised from 8.9 to > 9.5. The uptake in vitro of the 125I-labeled native D146 antibody by MDA-MB231 human carcinoma cells was negligible, whereas there was a marked increase in the endocytosis of the antibody following cationization. In vivo pharmacokinetic analysis was performed in male BALB/c mice. The in vivo organ uptake of the cationized monoclonal antibody was increased relative to the native antibody; there was a 6-fold increase in the systemic volume of distribution, a 58-fold increase in the systemic clearance of the cationized antibody from the plasma compartment, and a 9-fold reduction in the mean residence time of the cationized antibody as compared to the native D146 antibody. In conclusion, these studies show that cationization of an oncogene-specific monoclonal antibody results in markedly increased endocytosis of the antibody by cancer cells in vitro and in increased systemic clearance and organ uptake in vivo.