Conditionally Cleavable Radioimmunoconjugates: A Novel Approach for the Release of Radioisotopes from Radioimmunoconjugates

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• 作者：Craig Beeson ; James E. Butrynski ; Michael J. Hart ; Cynthia Nourigat ; Dana C. Matthews ; Oliver W. Press ; Peter D. Senter ; and Irwin D. Bernstein
• 刊名：Bioconjugate Chemistry
• 出版年：2003
• 出版时间：September 2003
• 年：2003
• 卷：14
• 期：5
• 页码：927 - 933
• 全文大小：113K
• 年卷期：v.14,no.5(September 2003)
• ISSN：1520-4812

文摘

One of the limitations of therapy with radiolabeled monoclonal antibodies (mAbs) is that significanttoxicities can arise from circulating non-tumor-bound radiolabeled conjugate. Here, we describe anew method to reduce systemic radiation exposure from radiolabeled mAbs involving the attachmentof the radioisotope through a linker that can be cleaved by an administered enzyme. To demonstratethe feasibility of this approach, we prepared a conditionally cleavable radioimmunoconjugate (RIC)composed of ¹³¹I-labeled cephalosporin conjugated to Tositumomab, a mAb against the CD20 antigen.The cleavable RIC bound antigen identically to directly iodinated antibody, and in the presence ofges/gifchars/beta2.gif" BORDER=0 ALIGN="middle">-lactamase, about 80-85% of the radioisotope was released. In vivo studies in mice revealed thatthe cleavable RIC and the directly iodinated anti-CD20 antibody had similar biodistribution patterns.Systemically administered ges/gifchars/beta2.gif" BORDER=0 ALIGN="middle">-lactamase induced a 2-3-fold decrease in the percent injected dose (ID)of the cleavable RIC/g of blood, marrow, spleen, lung, and liver 1 h after enzyme treatment, and a4-6-fold decrease 20 h after enzyme treatment. This was accompanied by a 20-fold increase in %ID/g in urine 1 h after enzyme treatment, indicating that the released radiolabel was rapidly excretedthrough the kidneys. In mice with human tumor xenografts, there was no decrease in the %ID/g intumor 1 h after enzyme treatment, but by 4 h after enzyme injection, decreases in tumor radioactivecontent began to diminish the targeting advantage. These studies demonstrate that the cleavableRIC substrate is able to bind to tumor antigens and localize within human tumor xenografts and thataccelerated systemic clearance can be induced with ges/gifchars/beta2.gif" BORDER=0 ALIGN="middle">-lactamase.