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Junghans 677
The site on Fc for interaction with the FcRp is distinct from the sites for binding
complement or hematopoietic FcR. Accordingly, it is possible to design Fc-
containing molecules or to modify therapeutic IgG that will delete unwanted
immune system interactions while preserving the long survival properties of IgG.
For example, it has been hypothesized that such immune system interactions may
have led to the excess deaths in one population of patients treated with TNF
receptor-Fc chimeras, that such modifications might have helped to avoid. 22
Aware of these features of IgG catabolism, one may consider finally the
interplay between the biologic half-life, determined by the survival of antibody or
antibody fragments, and the physical half-life, determined by the isotope decay, in
estimating the efficacy and exposure to normal tissues. In general, when the t m of
the antibody is less than that of the radioisotope (e.g., Fab), then the site of
catabolism of the antibody will indicate the site of greatest potential exposure to the
radioactivity. In general, the site of catabolism is either the kidney for filtered
antibodies, or diffusely in the body (as vascular endothelium) for intact, nonfiltered
antibody. In practice, there are few situations in which the therapeutic isotope has
a half-life that exceeds that of complete immunoglobulins in humans, whether it be
IgG, IgA, or IgM, which have minimum 5-day half-lives. On the other hand, where
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antibody catabolism is slow relative to isotope decay (e.g., Y IgG), the exposure
to the kidney is less and whole-body toxicities, typically marrow, are what are
dose-limiting. (The presence of murine glycosylation patterns on intact mouse IgG
has been thought to divert these antibodies at least in part to the liver, but this is
considered less of a factor in the evolving predominance of human antibodies.) The
damage to normal tissue is mitigated where the isotope itself is excreted from the
body after antibody catabolism with a time constant substantially more rapid than
the isotope decay (e.g., 131
I), and conversely the damage to the organ is enhanced
where the isotope is efficiently retained in the catabolic tissue until decay (e.g.,
212
Pb). Some isotopes when liberated are chemically disposed to particular tissues
for uptake, such as iodine to thyroid and yttrium to bone. However, strategies such
as chemical blockade with KI and better chelators have greatly ameliorated these
tendencies. In terms of targeting, it is important that the balance of biologic and
physical half-lives are compatible with the objectives of tissue penetration, tumor
concentration, and adequate dose delivery compatible with safety. While these
kinetic features were previously recognized, the new understanding of the
mechanisms of catabolism of IgG and its fragments will ultimately contribute to the
rational design of antibody-based radioimmunotherapies.
REFERENCES
1. Junghans RP: Finally! The Brambell receptor (FcRB): Mediator of transmission of immu­
nity and protection from catabolism for IgG. Immunol Res 16:29-57, 1997.