(6-Maleimidocaproyl)hydrazone of doxorubicin--a new derivative for the preparation of immunoconjugates of doxorubicin.
The (6-maleimidocaproyl)hydrazone of doxorubicin was synthesized and conjugated to several mAbs, including chimeric BR96, via a Michael addition reaction to thiol-containing mAbs. DTT reduction of disulfides present in the mAb was a reliable and general method for generating a consistent number of reactive SH groups. The conjugates, after purification by Bio-Beads, were free of unreacted linker and/or doxorubicin. All conjugates released doxorubicin under acidic conditions that mimic the lysosomal environment, while they were relatively stable at neutral pH. BR96 conjugates showed antigen-specific cytotoxicity.
Willner
D
D
Bristol-Myers Squibb Company, Wallingford, Connecticut 06492-7660.
Trail
P A
PA
Hofstead
S J
SJ
King
H D
HD
Lasch
S J
SJ
Braslawsky
G R
GR
Greenfield
R S
RS
Kaneko
T
T
Firestone
R A
RA
D000230:Adenocarcinoma / Q000188:drug therapy / Q000276:immunology; D000818:Animals; D000911:Antibodies, Monoclonal / Q000378:metabolism; D003432:Cross-Linking Reagents / Q000138:chemical synthesis* / Q000737:chemistry; D004229:Dithiothreitol / Q000737:chemistry; D004317:Doxorubicin / Q000031:analogs & derivatives* / Q000138:chemical synthesis / Q000737:chemistry / Q000378:metabolism / Q000633:toxicity*; D004355:Drug Stability; D000939:Epitopes; D006801:Humans; D006835:Hydrazones / Q000138:chemical synthesis* / Q000737:chemistry; D000922:Immunotoxins / Q000737:chemistry* / Q000378:metabolism / Q000633:toxicity*; D008175:Lung Neoplasms / Q000188:drug therapy / Q000276:immunology; D051379:Mice; D010084:Oxidation-Reduction; D013438:Sulfhydryl Compounds / Q000737:chemistry
D000911:Antibodies, Monoclonal; D003432:Cross-Linking Reagents; D000939:Epitopes; D006835:Hydrazones; D000922:Immunotoxins; D013438:Sulfhydryl Compounds; C085780:doxorubicin(6-maleimidocaproyl)hydrazone; D004317:Doxorubicin; D004229:Dithiothreitol