A major disadvantage of (131)
iodine (I)-labeled
monoclonal antibodies (MAbs) for
radioimmunotherapy has been the rapid diffusion of
iodotyrosine from target cells after internalization and catabolism of the radioiodinated MAbs. We recently reported that a radioiodinated, diethylenetriaminepentaacetic
acid-appended
peptide, designated immunomedics' residualizing
peptide 1 (IMP-R1), was a residualizing
iodine label that overcame many of the limitations that had impeded the development of residualizing
iodine for clinical use. To determine the factors governing the therapeutic index of the labeled MAb, as well as the factors required for production of radioiodinated MAb in high yield and with high specific activity, variations in the
peptide structure of IMP-R1 were evaluated. A series of radioiodinated, diethylenetriaminepentaacetic
acid-appended
peptide moieties (IMP-R1 through IMP-R8) that differed in overall hydrophilicity and charge were compared. Radioiodinations of the
peptides followed by conjugations to
disulfide-reduced RS7 (an anti-epithelial
glycoprotein-1 MAb) furnished
radioimmunoconjugates in good overall incorporations, with immunoreactivities comparable to that of directly radioiodinated RS7. Specific activities of up to 8 mCi/mg and yields > 80% have been achieved. In vitro processing experiments showed marked increases in radioiodine retention with all of the adducts; radioiodine retention at 45 h was up to 86% greater in cells than with directly iodinated RS7. Each of the (125)I-peptide-RS7 conjugates was compared with (131)I-RS7 (labeled by the
chloramine-T method) in paired-label biodistribution studies in nude mice bearing human lung
tumor xenografts. All of the residualizing substrates exhibited significantly enhanced retention in
tumor in comparison to directly radioiodinated RS7, but the nontarget uptakes differed significantly among the residualizing labels. The best labels were IMP-R4 and IMP-R8, showing superior
tumor-to-non-
tumor ratios by virtue of high
tumor uptake and retention and low normal organ uptake, as well as superior radiochemical properties. The therapeutic efficacy of (131)I-IMP-R4-RS7 was compared with that of conventionally (131)I-labeled RS7 and (90)yttrium-RS7 in the nude mice
lung cancer model. The therapeutic efficacy of (131)I-IMP-R4-RS7 and (90)yttrium-RS7 were equivalent, and both agents yielded significantly improved control of
tumor growth compared with conventional (131)I-labeled RS7.