1996 Fiscal Year Final Research Report Summary
Metabolism-Based Design of Protein-and Peptide-Radiopharmaceuticals
| Project/Area Number |
07672419
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| Research Category |
Grant-in-Aid for Scientific Research (C)
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| Allocation Type | Single-year Grants |
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| Section | 一般 |
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| Research Field |
医薬分子機能学
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| Research Institution | KYOTO UNIVERSITY |
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Principal Investigator |
ARANO Yasushi Kyoto University, Dept.of Radiopharm.Chem.Associate Professor, 薬学部, 助教授 (90151167)
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| Project Period (FY) |
1995 – 1996
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| Keywords | monoclonal antibodies / peptides / lysosomal proteolysis / radiometabolites / radioiodine / radioimaging / radiotherapy / urinary excretion |
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| Research Abstract |
Recent advent of genetic engineering has provided humanized monoclonal antibodies (mAbs) and antibody fragments, which potentially solve various problems associated with the clinical use of mAbs derived from mice. Further development of radiochemistry of mAbs that reduce the unfavorable radioactivity localization in non-target tissues such as the liver can provide radiolabeled mAbs much more suitable to clinical applications. Our recent studies demonstrated that radiometabolites generated after lysosomal proteolysis in non-target tissues play a critical role in the unfavorable radioactivity levels of radiolabeled mAbs. It has also been well recognized that many mAbs against solid tumors do not or only slowly locate within tumor cells. On these bases, we disigned and synthesized radioiodination reagents for mAbs that provide stable attachment of radioiodine with mAbs in plasma while facilitating a rapid and selective release of meta-iodohippuric acid after lysosomal proteolysis in non-t
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arget tissues. Among various reagents, we finally developed 3'- (tri-n-butylstannyl) hippuryl-N-e-maleoyl-L-lysine (HML). This reagent possesses a maleimide group for site-specific conjugation with thiolated mAbs and an organo-tin group for high-yield radioiodination, and the two functional groups were linked with a peptide bond derived from L-lysine. When radioiodinated galactosyl-neoglycoalbumin (NGA) using HML as the reagent was administered into mice, the peptide bond of HML demonstrated selective cleavage at a rate similar to that of an ester bond. Furthemore, the peptide bond in HML was stable when incubated in freshly prepared human plasma for 24 h at 37ﾟC.These findings indicated that HML is the first reagent that provides stable attachment of a radiolabel with polypeptide in plasma while facilitating a rapid and selective release of the designed radiometabolite of high urinary excretion after lysosomal proteolysis. In biodistribution studies in nude mice, the radioiodinated mAbs with HML demonstrated decreased radioactivity levels in the liver without impairing radioactivity levels in the target. As a result, the HML-labeled mAb indicated much higher target-to-non-target ratios of the radioactivity when compared with radiolabeled mAbs investigated so far. The gathered findings indicated that HML would be useful for not only diagnostic purposes with I-123 but for therapeutic purposes with I-131 when combined with mAbs or oncophilic peptides. These findings also indicated that the radiochemical design of polypeptide and peptides using metabolizable linkages would possess high potentiality to further development of radiolabeled oncophilic molecules for clinical applications. Less
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