In vivo behaviour of antibody-drug conjugates for the targeted treatment of cancer.
It is a commonly held belief that most treatments for disseminated cancers are only moderately effective because the agents lack cell-killing mechanisms that act specifically on cancer cells. In antibody-drug conjugates, such nonspecific cytotoxic agents are combined with exquisitely specific monoclonal antibodies that bind to tumour-associated antigens and, thus, get endowed with new pharmacological characteristics. Not only is their activity newly targeted towards tumours and tumour cells, which hopefully renders them more tumour-specific, but they also acquire much of the pharmacokinetic behaviour of the monoclonal antibody component. With the structural composition of a macromolecular protein (the antibody), a small chemical cytotoxic agent and a linker to chemically connect these two molecules, antibody-drug conjugates are some of the most complex pharmacological agents ever developed. Their development over the last 20 years or so owes much to sophisticated in vitro and in vivo preclinical testing. This review attempts to summarise and exemplify many of the factors that had to be considered during the development, with special emphasis on the in vivo pharmacology of these agents.
Xie
Hongsheng
H
ImmunoGen, Inc., Cambridge, MA 02139, USA. hongsheng.xie@immunogen.com
Blättler
Walter A
WA
D000818:Animals; D000912:Antibodies, Neoplasm / Q000008:administration & dosage* / Q000378:metabolism*; D000970:Antineoplastic Agents / Q000008:administration & dosage*; D016503:Drug Delivery Systems / Q000379:methods*; D006801:Humans; D018796:Immunoconjugates / Q000008:administration & dosage*; D009369:Neoplasms / Q000188:drug therapy* / Q000276:immunology* / Q000378:metabolism
D000912:Antibodies, Neoplasm; D000970:Antineoplastic Agents; D018796:Immunoconjugates