Increased serum stability and prolonged biological half-life of neocarzinostatin covalently bound to monoclonal antibodies.
The pharmacokinetics of neocarzinostatin (NCS) have been compared to NCS conjugates with monoclonal antibodies using Balb/c and tumor bearing nude mice. Data on blood and whole body clearance revealed that the high MW conjugate persists in the body far longer and at a higher level than the free drug. Excretion of the free drug occurs with an extremely rapid renal clearance and localization of the remaining drug in the kidney, whereas the NCS immunoconjugate remained in circulation far longer allowing time for tumor localization to occur without renal accumulation of drug. In addition, NCS conjugated to monoclonal antibody was found to retain its activity in human serum better than free drug, in agreement with data obtained for other NCS-derivatives. Half-time of inactivation was greatly extended when measured under relevant conditions in a DNA strand-break assay. The results indicate that two of the most important requirements for the successful targeting of NCS in vivo, decreased clearance rate and increased serum stability are achieved by conjugation to antibody. Both results increase the probability of NCS accumulating in tissue while still in its active form. Coupling of NCS to monoclonal antibody decreases clearance and inactivation rate and increases localization of the active drug in tumor tissue.
Gottschalk
U
U
Institut für Strahlenbiologie, Westfälische Wilhelms-Universität Münster, Germany.
Garnett
M C
MC
Ward
R K
RK
Maibücher
A
A
Köhnlein
W
W
D000818:Animals; D000903:Antibiotics, Antineoplastic / Q000097:blood*; D000911:Antibodies, Monoclonal / Q000097:blood* / Q000378:metabolism; D006207:Half-Life; D006801:Humans; D007275:Injections, Intravenous; D007700:Kinetics; D051379:Mice; D008807:Mice, Inbred BALB C; D008819:Mice, Nude; D009152:Mutagenicity Tests; D014018:Tissue Distribution; D009353:Zinostatin / Q000097:blood* / Q000378:metabolism / Q000493:pharmacokinetics
D000903:Antibiotics, Antineoplastic; D000911:Antibodies, Monoclonal; D009353:Zinostatin