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Improved Iodine Radiolabels for Monoclonal Antibody Therapy¹

Garden State Cancer Center, Belleville, New Jersey 07109 [R. S., M. J. M., S. C., L. R., G. N., D. M. G.], and Immunomedics, Inc., Morris Plains, New Jersey 07950 [S. V. G., B. J. M., G. L. G., H. J. H.]

A major disadvantage of ¹³¹iodine (I)-labeled monoclonal antibodies (MAbs) for radioimmunotherapyhas been the rapid diffusion of iodotyrosine from target cells afterinternalization 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 ¹²⁵I-peptide-RS7 conjugates was compared with ¹³¹I-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 ¹³¹I-IMP-R4-RS7 was compared with that of conventionally ¹³¹I-labeled RS7 and ⁹⁰yttrium-RS7 in the nude mice lung cancer model. The therapeutic efficacy of ¹³¹I-IMP-R4-RS7 and ⁹⁰yttrium-RS7 were equivalent, and both agents yielded significantly improved control of tumor growth compared with conventional ¹³¹I-labeled RS7.

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