The second time around. Implementing successful technology sometimes means starting over.
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Diffusion of Innovation↗
Biomedical subjects
Linda Reed
Publications and source records attributed to Linda Reed.
Improved iodine radiolabels for monoclonal antibody therapy.
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.
Adenocarcinoma↗
Combining radioimmunotherapy and chemotherapy for treatment of medullary thyroid carcinoma: effectiveness of dacarbazine.
BACKGROUND: To enhance the efficacy of chemotherapy for medullary thyroid carcinoma (MTC), we evaluated the effect of combining radioimmunotherapy (RAIT) with 90Y-anticarcinoembryonic antigen (CEA) monoclonal antibody MN-14 and chemotherapy in nude mice bearing human MTC xenografts. A preliminary study evaluated doxorubicin, dacarbazine (DTIC), cyclophosphamide, and vincristine, singly and in combination, for their effect on the growth of MTC xenografts (TT) in nude mice. Given individually, DTIC yielded the most effective tumor growth inhibition, delaying the mean time to doubling from 1 week for untreated tumor-bearing mice to 7.5 weeks. Administering either the 4 drugs in combination or a 2-drug combination comprised of doxorubicin and DTIC significantly improved the efficacy compared with any single drug alone, increasing the mean doubling time to 10-12 weeks. METHODS: Drug doses were selected to conform to the doses of each drug given clinically. For the combined modality therapy, administration of 90Y-labeled anti-CEA monoclonal antibody MN-14 to nude mice bearing established TT tumors was followed by various chemotherapy regimens initiated 24 hours after RAIT. Chemotherapy protocols combined with RAIT included doxorubicin or DTIC alone and in combination, and the doxorubicin, DTIC, cyclophosphamide, and vincristine 4-drug protocol. Tumor volumes were measured weekly, and toxicity was evaluated by measuring blood counts and body weight. RESULTS: Combinations of RAIT and chemotherapy with DTIC or RAIT and chemotherapy with the drug combinations were found to augment the antitumor effects of RAIT or chemotherapy alone, without a significant increase in toxicity. The mean tumor volume doubling times were increased up to 100% compared with the results of chemotherapy alone. No significant differences in tumor growth were observed between the RAIT plus DTIC protocol and the RAIT plus two- or four-drug protocols. CONCLUSIONS: The superiority of the combined modality treatment argues for the integration of RAIT into chemotherapeutic regimens for MTC treatment. Clinical trials are needed to assess these principles in MTC patients.
Animals↗