PHARMACODYNAMICS OF RECOMBINANT HUMAN DNASE-I IN SERUM

Recombinant human deoxyribonuclease I (rkDNase) may be an effective th erapeutic for the treatment of systemic lupus erythematosus (SLE). The pharmacodynamics of rhDNase in serum was investigated using two activ ity assays: one based on hydrolysis of a radiolabelled phage DNA and t he other based on hydrolysis of human chromatin. The concentration of endogenous immunoreactive DNase in sera from 16 normal subjects was 3. 2 @ 1.4 ng/ml (mean @ s.d.); however, low levels or no nuclease activi ty were detected in the same sera, suggesting the presence of DNase in hibitors. We assessed the ability of rhDNase to degrade DNA in undilut ed serum, since the observed inhibition of endogenous DNase was revers ed upon dilution. Addition of rkDNase to undiluted serum at a concentr ation of 50-100 ng/ml was necessary for degradation of radiolabelled p hage DNA. The activity of rhDNase added to serum from normal subjects and SLE patients was similar, rhDNase degraded human chromatin and chr omatin/anti-DNA immune complexes in serum with similar potency (EC50 a pproximate to 100-200 ng/ml). A 500-fold variation in the chromatin/an ti-DNA stoichiometry did not significantly affect the digestion of the se immune complexes by rhDNase in buffer. These results indicate that a minimum rhDNase concentration of 50-100 ng/ml in serum was required to achieve detectable catalytic activity and that tie presence of anti bodies to DNA did not inhibit the degradation of DNA/anti-DNA immune c omplexes.