| Big Picture: |
Radioimmunotherapy (RAIT) is an approach to cancer treatment that
combines the tumor-targeting properties of monoclonal antibodies
with the cell-destroying capabilities of radioactive substances.
While RAIT has had some success in curbing diffuse malignant diseases,
it has not proven effective against solid tumors. Problems inherent
in treating solid tumors with RAIT include the large size of intact
monoclonal antibodies, their prolonged circulation and poor targeting
specificity, and the mismatch between the half-lives for the monoclonal
antibodies and the radioisotopes. Researchers have developed smaller
antibody-based proteins, called diabodies. Due to their small size,
diabodies are rapidly eliminated from circulation and expected to
penetrate tumors more easily than intact monoclonal antibodies. |
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| Focus: |
The authors of this study have developed a diabody known as
C6.5, which targets the human tumor-associated antigen HER2/neu that is overexpressed in breast and ovarian tumors. When joined
to an extremely short-lived, a-emitting radioactive molecule in
an earlier investigation, the C6.5 diabody failed to target the
tumor cells in animals fast enough to be an effective therapy.
In the current study, the authors examined the anti-tumor effects
of C6.5 when linked with a longer-lasting, ß-emitting radioisotope.
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| Findings: |
The results of this study show that a single treatment of the ß-emitting
isotope yttrium-90 joined to the C6.5 diabody substantially inhibits
the growth rates of breast tumors in mice. However, the same treatment
caused only a minor delay in the growth of ovarian tumors in mice.
The different responses of the two tumor models to could be due to
several differences between the tumor cell lines, including the rate
at which HER2/neu is internalized after diabody binding, radiation
sensitivity, tumor size, and p53 status. Findings from additional
experiments in this study suggest that high renal retention of the
diabody molecule may make it toxic at high doses. |
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| Conclusions: |
These studies suggest that diabody-based RAIT can be an effective
form of cancer treatment. They provide the first demonstration that
diabody molecules can be effective targeting vehicles for the RAIT
of solid tumors. |
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| Next Steps: |
Since long-term renal damage may be a complication of diabody-based
RAIT, additional studies with larger numbers of mice will be needed
to assess this potential risk. In addition, because this research
indicates that antigen (in this case HER2/neu) expression is not
the only factor that predicts the success of RAIT, it will be important
to elucidate the other factors involved. |
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| Study Team: |
Medical/Preclinical Scientists, Fox Chase Cancer Center
Chemists, National Cancer Institute, NIH
Molecular Biologists, University of California at San Francisco
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| Citation: |
Adams, G.P., Shaller, C.C., Dadachova, E., Simmons, H.H., Horak,
E.M., Tesfaye, A., Klein-Szanto, J.P., Marks, J.D., Brechbiel, M.W.,
and Weiner, L.M. “A Single Treatment of Yttrium-90-labeled
CHX-A”-C6.5 Diabody Inhibits the Growth of Established Human
Tumor Xenografts in Immunodeficient Mice.” Cancer Research,
Vol. 64, Sept. 1, 2004. |
