EFFECTS OF RECOMBINANT DRUG-SPECIFIC SINGLE-CHAIN ANTIBODY FV FRAGMENT ON [H-3] DESIPRAMINE DISTRIBUTION IN RATS

Tricyclic antidepressant overdose can be reversed in rats by drug-spec ific antibody Fab fragments, but the required Fab dose may itself be t oxic. We studied the potential use of a smaller, recombinant desiprami ne (DMI)-specific single chain Fv fragment (B9-sFv) for this purpose. Anesthetized rats received a tracer (subtoxic) dose of [H-3]-DMI follo wed in 15 min by B9-IgG, B9-Fab, B9-sFv (0.1 mu mol of binding sites), or BSA. Each of the active treatments produced a rapid and substantia l increase in the serum radiolabel concentration, whereas BSA did not (P < 0.001). The increase in serum radiolabel concentration 1 min afte r treatment was 13.3-fold with B9-IgG, 10.0-fold with BB-Fab and 7.3-f old with B9-sFv. Serum antibody concentrations were also highest after B9-IgG and lower with B9-Fab or B9-sFv. The 24-hr urinary excretion o f radiolabel did not differ among groups, but was extensive even in th e BSA group and probably represented the excretion of DMI metabolites. B9-sFv concentrations in urine or buffer at 37 degrees declined by >9 0% over 24 hr, but this fragment was much more stable in serum, retain ing 70% of its activity after 96 hr. These data demonstrate that B9-sF v can alter markedly the distribution of [3H] DMI in vivo. The rapidit y of this effect, and its magnitude in comparison with Fab fragment or IgG, suggest that further study of B9-sFv as a treatment of DMI overd ose is warranted.