Pretargeting Strategies

In order to enhance the efficacy of RIT, multistep targeting strategies have been under development. These methods are designed to minimize the radiation to normal tissue that is attributed to prolonged residence time in the body. One approach utilizes the interaction of avidin and biotin. The pretargeting tumor-specific antibody/avidin fusion protein is administered. After the circulating antibody has been cleared with a clearing agent, radiolabeled biotin is injected. This process attaches to the streptavidin on the tumor surface (Fig. 4).

Early studies of pretargeted RIT, designed to evaluate its safety and therapeutic ratio, demonstrated a mean tumor to marrow absorbed dose ratio of 63:1, which is an order of magnitude greater than the 6:1 ratio, usually seen in conventional RIT (92). Studies of pretargeted treatment with monoclonal antibody NR-LU-10-streptavidin (constructed as a tetrameric sFv bound to streptavidin) and 90Y-biotin in refractory colorectal adenocarcinoma demonstrated mean tumor absorbed dose of 0.5 + 0.2 cGy/MBq, which was significantly higher than the dose estimate to the kidney 0.3 + 0.1 cGy/MBq and to the bone marrow (0.1 mGy/MBq). Despite these impressive ratios, only 8% of the patients showed a major response to therapy. Although hematologic toxicity was not dose limiting, nonhematologic toxicities were significant (93), underscoring that this technique will not spare normal tissues that express antigen. It is

Figure 4 Tumor pretargeting with bispecific construct: a bispecific agent (e.g., bispecific antibody or an antibody/streptavidin fusion) is administered, which saturates the antigen on the tumor. Subsequently, a small radionuclide carrier is administered, which binds to the tumor-localizing bispecific agent.

Figure 4 Tumor pretargeting with bispecific construct: a bispecific agent (e.g., bispecific antibody or an antibody/streptavidin fusion) is administered, which saturates the antigen on the tumor. Subsequently, a small radionuclide carrier is administered, which binds to the tumor-localizing bispecific agent.

anticipated that dose-limiting toxicity with these multistep techniques will likely be renal. This poses additional issues as nephropathy is usually not evident until several years after renal insult, and it is thus difficult to evaluate nephrotoxicity in the treatment setting. Finally, avidin and streptavidin are immunogenic. This limits the administration of the initial agent to single use. Such multistep targeting methods are therefore analogous to external beam therapy in that they can be used over one course with no possibility for retreatment.

Promising results using the pretargeting approach have been shown in gliomas. Studies of biotinylated anti-tenascin monoclonal antibody, with 90Y-dodecane tetraacetic acid (DOTA) biotin as the radionuclide, have demonstrated response as sole therapy for recurrent disease and in the adjuvant setting (94).

Bispecific constructs that react against a radiometal-chelate complex, on the other hand, are unlikely to be immunogenic, and therefore hold promise as therapeutic agents (95,96). These novel systems should be able to deliver higher amounts of relative tumor radiation-absorbed dose than would be possible with single-step radiolabeled antibody methods. They may have the added advantage of less immunogenicity of avidin-based systems, allowing multiple/repeat therapies.

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