Abstract
A colorectal tumour-directed immunotoxin, ICI D0490, has been constructed by linking recombinant ricin A-chain to C242, a mouse monoclonal antibody, by means of a methyl-hindered disulphide bond. Recombinant ricin A-chain and a hindered disulphide linker were anticipated to confer favourable pharmacokinetic properties on the immunotoxin. The pharmacokinetics of ICI D0490 have been studied in mice following single and repeated i.v. administration. The concentrations of intact immunotoxin in mouse plasma at various time intervals after injection for up to 96 h were measured by a solid-phase enzyme-linked immunosorbent assay (ELISA) and the data analysed by both model-dependent (two compartment) and model-independent methods. Following a single i.v. bolus dose of 2.5 mg kg-1 (50% of the LD10 in mice), the clearance of ICI D0490 from the plasma was extremely slow; 34 microliters min-1 kg-1, t1/2 beta = 33 h. Model-dependent and model-independent analyses gave comparable results with steady state volumes of distribution of 93 and 69 ml kg-1, respectively. The two compartment analysis gave an initial volume of distribution (63 ml kg-1) which is consistent with the predicted plasma volume. Over the dose range 0.05-5 mg ICI D0490 kg-1, plasma levels at 2 and 24 h were linearly related to dose (r > or = 0.98) indicating that at doses up to 5 mg ICI D0490 kg-1 clearance does not appear to have a saturable component. Repeated doses of ICI D0490 (1 mg kg-1 day x 5) did not lead to drug accumulation. These studies demonstrate that ICI D0490 has excellent in vivo stability and persistence which, in conjunction with activity and toxicity data, identify ICI D0490 as a promising candidate for clinical evaluation in the treatment of colorectal cancer.
Highlights
(Byers et al, 1989; Gould et al, 1989; Hertler et al, 1988; Pai et al, 1991; Spitler et al, 1987; Vitetta et al, 1991; Weiner et al, 1989)
This paper reports the pharmacokinetic characteristics of ICI D0490 in non-tumour bearing mice after intravenous administration
The lethal toxicity was delayed for about three days after dosing which enabled a single dose of 5 mg kg' to be safely administered for characterisation of initial plasma levels of ICI D0490
Summary
(Byers et al, 1989; Gould et al, 1989; Hertler et al, 1988; Pai et al, 1991; Spitler et al, 1987; Vitetta et al, 1991; Weiner et al, 1989). The problems that have been encountered include poor tumour specificity of the conjugate resulting in antibody-directed normal tissue toxicity (Gould et al, 1989; Pai et al, 1991) and immunotoxin-induced capillary leak syndrome, observed in most studies. Where acceptable patient tolerance of immunotoxins has been achieved, no consistent anti-tumour activity has been observed with the exception of a pan B-cell-directed ricin A-chain immunotoxin for the treatment of B-cell lymphoma (Vitetta et al, 1991)
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