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Selection of Radioisotopes, Chelates and
Immunoconjugates for Radioimmunotherapy
RE. Borchardt
The Arlington Cancer Center, Arlington, TX
Interest in radioimmunotherapy (RIT) has increased following positive clinical
results in hematologic malignancies. This presents an opportunity to reexamine the
optimal selection of radioisotopes, chelates, and immunoconjugates for clinical RIT.
Radiometals. The pure beta emitter, yttrium-90, is replacing iodine-131 for the
treatment of measurable disease. Yttrium-90 can be administered on an outpatient
basis and is readily available carrier-free at high specific activity. Lutetium-177 has
less energetic beta emissions that could be exploited for the treatment of
microscopic disease. Both radioisotopes can be attached to proteins through bifunctional
chelates.
Chelates. Two types of chelates have been developed: backbone substituted
DTPA derivatives and macrocyclics. The first rapidly complex trivalent
radiometals, at high yield and with little interference from contaminating metal ions.
In contrast, the macrocyclics complex radiometals more slowly, at reduced yields,
and are sensitive to trace metal contamination. However, macrocyclic/radiometal
complexes have higher in vivo stability. Chelates can be immunogenic, but their
immunogenicity is dependent on that of the administered antibody.
Immunoconjugates. The biologic half-life of an administered antibody reflects
the half-life of the antibody class in the species of origin. In general, the half-life
increases with species size. Smaller-sized radioimmunoconjugates: scFv, dimeric
Fv, Fab' and F(ab') 2 target tumor faster and more homogeneously than IgG but also
have lower tumor uptake due to their shorter blood half-lives. Smaller radioimmunoconjugates
will only be valuable for therapy if their tumor uptake and
retention can be increased. Tumor retention is positively correlated to the number
of antigen binding sites. Dimeric Fv and F(ab') 2 demonstrate longer tumor
retention than scFv and Fab'. The intracompartmental (i.e.) and intralesional (i.l.)
administration of radioimmunoconjugates bypasses the delivery problem posed by
the endothelial barrier. Both i.e. and i.l. administration can provide higher tumor
uptake (>80% injected dose per gram of tumor). Tumor retention of i.e. and i.l.
administered radioimmunoconjugates is based on size and the number of antigen
binding sites, with IgM having higher retention than IgG.
Conclusion. Higher therapeutic ratios for clinical RIT will be possible through
judicious selection and preclinical testing of radioimmunoconjugate components.
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