Conjugation of anticancer drugs through endogenous monoclonal antibody cysteine residues.
Many methods have been described for the conjugation of drugs to monoclonal antibodies. The presence of a discrete number of readily reducible disulfides in the common IgG subtypes presents a convenient opportunity for conjugation to cysteine residues with thiol-reactive drug-linkers. Such conjugates can be prepared by a straightforward two-step reaction scheme involving the reduction of the antibody disulfides to the desired number of average thiols per antibody, followed by addition of the drug-linker, ideally with a maleimido functionality for rapid, selective reaction. In a discovery setting, this basic method can be scaled down to produce microgram quantities of conjugate for early screening, and in a manufacturing setting can be scaled up to produce grams or kilograms of conjugate for clinical trials and commercialization. The resulting conjugates are readily characterized using common HPLC methods.
Seattle Genetics, Bothell, Washington, USA.
Robert P
RP
Lyon
David L
DL
Meyer
Jocelyn R
JR
Setter
Peter D
PD
Senter
D000818:Animals; D000911:Antibodies, Monoclonal / Q000737:chemistry* / Q000276:immunology / Q000378:metabolism / Q000494:pharmacology; D000941:Antigens / Q000276:immunology / Q000378:metabolism; D000970:Antineoplastic Agents / Q000737:chemistry* / Q000276:immunology / Q000378:metabolism / Q000494:pharmacology; D045744:Cell Line, Tumor; D002851:Chromatography, High Pressure Liquid; D003432:Cross-Linking Reagents / Q000737:chemistry; D003545:Cysteine / Q000737:chemistry / Q000378:metabolism*; D004220:Disulfides / Q000737:chemistry / Q000378:metabolism; D004337:Drug Carriers / Q000737:chemistry / Q000378:metabolism* / Q000494:pharmacology; D005033:Ethylmaleimide / Q000737:chemistry; D006801:Humans; D006825:Hybridomas / Q000276:immunology / Q000378:metabolism; D055767:Immobilized Proteins / Q000737:chemistry* / Q000378:metabolism; D018796:Immunoconjugates / Q000737:chemistry / Q000378:metabolism* / Q000494:pharmacology; D051379:Mice; D015394:Molecular Structure; D009369:Neoplasms / Q000188:drug therapy* / Q000276:immunology / Q000378:metabolism / Q000473:pathology; D010084:Oxidation-Reduction; D013439:Sulfhydryl Reagents / Q000737:chemistry
D000911:Antibodies, Monoclonal; D000941:Antigens; D000970:Antineoplastic Agents; D003432:Cross-Linking Reagents; D004220:Disulfides; D004337:Drug Carriers; D055767:Immobilized Proteins; D018796:Immunoconjugates; D013439:Sulfhydryl Reagents; D003545:Cysteine; D005033:Ethylmaleimide