PHARMACOKINETICS OF MONOCLONAL IMMUNOGLOBULIN G1, F(AB')2, AND FAB' IN MICE

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  • 1 August 1986
    • journal article
    • research article
    • Vol. 46  (8) , 3969-3978
Abstract
The pharmacokinetics of an immunoglobulin G1 (IgG1) and its F(ab'')2 and Fab'' fragments following i.v. administration in mice has been studied by constructing a physiologically based, organ-specific model to describe antibody biodistribution, catabolism, and excretion. The antibody selected for study (MOPC-21) has no known binding sites in the body and therefore is useful for defining antibody metabolism by nontumor tissues. Whole IgG (a) remains in the body 8.3 days, the majority of time in the carcass (53.0% of the total residence time); (b) has a distribution volume exceeding that of plasma plus interstitial fluid; (c) distributes into these volumes rapidly for most enteral organs (equilibration time < 2.6 min for liver, spleen, kidney, and lung), slower for the gut (< 20 min); and slowest for carcass (< 260 min); (d) produces interstitial:plasma concentration ratios of > 0.5 for enteral organs and 0.18 for carcass; (e) has the greatest percentage of its catabolism due to the gut (72.8%), followed by the liver (20.5%), then the spleen (3.6%); (f) has the highest extraction on a single pass by the gut (0.14%) and (g) cycles through the interstitial spaces of the body at least 2.8 times/g of organ weight before being metabolized or excreted. When compared with whole IgG, the Fab'' fragment (a) is cleared from the body 35 times faster; (b) has a larger total distribution volume; (c) distributes more rapidly into this volume; (d) produces higher interstitial:plasma concentration ratios; (e) is catabolized principally by the kidney (73.4% of total catabolism), followed by the gut (22.9%), then the spleen (3.1%); (f) is extracted from the circulation to the extent of 3.4% on each pass through the kidney, and less by gut (1.0%) and spleen (0.14%) and (g) cycles through non-kidney interstitial spaces at least 0.4 cycles/g of tissue weight before metabolism or excretion. The F(ab'')2 fragment has pharmacokinetic characteristics that fall between those of whole IgG and Fab''. These results (a) provide pharmacokinetic criteria for selecting whole IgG, F(ab'')2, or Fab'' for various in vivo applications; (b) provide a framework for predicting cumulative tissue exposure to antibody labeled with different isotopes; and (c) provide a reference metabolic state for the analysis of more complex systems that do include antibody binding.