Biodistribution and plasma survival in mice of anti-melanoma monoclonal antibody cross-linked to OKT3.
Anti-melanoma monoclonal antibody XMMME-001 was cross-linked to anti-CD3 monoclonal antibody OKT3 with succinimidyl 3(2-pyridyldithio)propionate (SPDP), and 2-iminothiolane. The dimer heteroconjugate was purified by HPLC gel filtration, labeled with 131I, and 10 micrograms was injected into each of 24 BALB/c mice. The dimeric heteroconjugate's blood survival in sequentially bled mice (n = 3) and its biodistribution in organs of sacrificed mice (n = 21) were studied. In plasma, the heteroconjugate showed an alpha phase with a half-life of 4 h, and a beta phase with a half-life of about 18 h. Electrophoretic analysis of labeled heteroconjugate in plasma showed that the half-life of disulfide bonds linking the monoclonal antibodies was approximately 7-8 h. Radioactive heteroconjugate accumulated primarily in the liver; significant uptake was also seen in white blood cells and spleen. Very little radioactivity accumulated in kidney, lung, or colon. As a comparison, SPDP-derivatized anti-melanoma antibody was studied by the same methods. It showed an average alpha-phase half-life of 12.5 h; its maximum accumulation in liver or white blood cells was less than 30% of that of the heteroconjugate. Very low levels accumulated in other tissues. The results imply that the shorter half-life in plasma of the heteroconjugate is primarily determined by clearance due to its larger size and conformation, not the lability of cross-linking disulfide bonds.
Winkler
M A
MA
Biotherapeutics Inc., Memphis, TN 38117.
Price
J O
JO
Foglesong
P D
PD
West
W H
WH
D000818:Animals; D000911:Antibodies, Monoclonal / Q000032:analysis*; D000912:Antibodies, Neoplasm / Q000276:immunology; D000945:Antigens, Differentiation, T-Lymphocyte / Q000276:immunology; D017252:CD3 Complex; D003432:Cross-Linking Reagents / Q000494:pharmacology; D004220:Disulfides / Q000097:blood; D004355:Drug Stability; D005260:Female; D006207:Half-Life; D000922:Immunotoxins / Q000097:blood / Q000493:pharmacokinetics*; D008545:Melanoma / Q000276:immunology*; D051379:Mice; D008807:Mice, Inbred BALB C; D010949:Plasma; D011948:Receptors, Antigen, T-Cell / Q000276:immunology; D013388:Succinimides / Q000494:pharmacology; D014018:Tissue Distribution
D000911:Antibodies, Monoclonal; D000912:Antibodies, Neoplasm; D000945:Antigens, Differentiation, T-Lymphocyte; D017252:CD3 Complex; D003432:Cross-Linking Reagents; D004220:Disulfides; D000922:Immunotoxins; D011948:Receptors, Antigen, T-Cell; D013388:Succinimides; C018151:N-succinimidyl 3-(2-pyridyldithio)propionate