Cleavable Linkers. Radionuclide is attached to the antibody using a cephalosporin-based linker that can be cleaved with b-lactamse.
We are developing improved techniques for radiolabeled antibody treatments of lymphomas in collaboration with Irwin Bernstein at the Fred Hutchinson Cancer Research Center. One promising technique for the treatment of lymphoma is the use of radiolabeled antibodies that bind a cell-surface antigen expressed on tumor cells. However, there is a significant problem with the current technology. Although some of the radiolabeled antibodies localize at the tumor, most remain cirgulating in the bloodstream for long periods. Thus, organs with high blood volumes (i.e., the lungs, liver and kidneys) receive a significant amount of collateral radionuclude exposure. One approach to minimize such exposure is extracorporal immunoadsorption, a method in which the blood is circulated through a column that binds antibodies. If this is done after tumor-trageting is maximal, collateral irradiation of high blood flow organs is significantly reduced. We have developed an alternate approach that avoids the need to recirculate blood. The radionuclide is attached to the antibody with a linker that can be enzymatically cleaved. Injection of the enzyme after tumor-targeting is achieved rapidly releases the radionuclide from antibodies circulating in the blood. The radionuclide is attached to a small molecule that is rapidly cleared by the kidneys and, thus, minimizing collateral exposure.
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Cleavable Linkers. Radionuclide is attached to the antibody using a cephalosporin-based linker that can be cleaved with b-lactamse. |
After some of the antibodies reach the
tumor, b-lactamse
is injected. the enzyme cleaves the linker and the released
radionuclide is rapidly cleared by the kidneys. The enzyme
is modified with polyethyleneglycol (PEG). The PEG modified
enzyme is less immunogenic and its ability to access the
extravascular spoaces is much reduced.
Cleavage of the lactam allows the
nitrogen lone pair to migrate leading to the fragmentation
of the carbamate. The linker attached to the antibody and
CO2 are released. Shown is the synthesis of cleavable
linker 1 that has been succesfully used in mice with
xenograft tumors. Upon injection of PEG-lactamase, about 85%
of the I131 is found in the urine after 30 min.
