Improvement in the therapeutic, immunological, and clearance properties of Escherichia coli and Erwinia carotovora L-asparaginases by attachment of poly-DL-alanyl peptides.
The chemical modification of both Escherichia coli and Erwinia carotovora asparaginases by a DL-alanine-N-carboxyanhydride polymerization technique produced modified enzymes which had greater protease stability, retained most of their catalytic activity, and demonstrated a 7- to 10-fold prolongation in plasma clearance properties in normal mice and rats. Concomitantly, plasma substrate depletion was also extended 5 to 13 days longer for the modified as compared with the native enzymes. For preparations of modified enzymes with plasma half-lives longer than 24 hr, the therapeutic activity was superior to that of the native enzymes. In addition, the modified E. coli preparations were less immunogenic in mice than was the native enzyme, and they cross-reacted with antibodies developed to the native enzyme to a 300-fold lesser degree, such that the modified enzyme still showed prolonged clearance in an animal which had been immunized previously to the native enzyme. The native enzyme was immediately cleared from the plasma of such immune animals, although hyperimmune animals would rapidly clear both the native and modified enzymes. Similarly, the modified E. carotovora enzyme would cross-react to a 500-fold lesser degree with antibodies developed against the native E. carotovora enzyme.
D000409:Alanine / Q000031:analogs & derivatives; D000818:Animals; D000917:Antibody Formation; D001215:Asparaginase / Q000008:administration & dosage* / Q000097:blood / Q000276:immunology; D003429:Cross Reactions; D004885:Erwinia / Q000201:enzymology; D004926:Escherichia coli / Q000201:enzymology; D007942:Leukemia, Experimental / Q000188:drug therapy; D008297:Male; D008657:Metabolic Clearance Rate; D051379:Mice; D010455:Peptides / Q000008:administration & dosage* / Q000097:blood / Q000276:immunology; D051381:Rats
D010455:Peptides; D001215:Asparaginase; D000409:Alanine