Antibody-cytotoxic agent conjugates: preparation and characterization.
Conjugates of antibodies with cytotoxic agents offer a targeted therapeutic strategy against cancer cells expressing target antigens. Several antibodies against various cancer cell-surface antigens have been conjugated with different cytotoxic agents that inhibit essential cellular targets such as microtubules or DNA. Antibody-cytotoxic agent conjugates (ACCs) against several types of cancer are currently in advanced stages of clinical trials and one, gemtuzumab ozogamicin (Mylotarg), is approved for the treatment of acute myeloid leukemia. The linker group connecting the antibody to the cytotoxic agent is an important feature of the ACC, modulating the release of the active cytotoxic agent in the targeted cell. Several linker strategies employed for ACCs in current clinical trials include cleavable linkers with disulfide, hydrazone, lysosomal protease-substrate groups, and non-cleavable linkers. This chapter describes the methods of preparation of conjugates of antibodies with small-molecule cytotoxic agents (maytansinoids, calicheamicin, and auristatins) bearing different linkers. Methods to evaluate the in vitro cytotoxicity and in vivo anti-tumor efficacy of ACC are described in brief. Analytical methods are described to evaluate the mechanism of cellular processing of the ACCs with different linkers and the generation of the active metabolites.
Singh
Rajeeva
R
ImmunoGen Inc., Waltham, MA, USA.
Erickson
Hans K
HK
D000818:Animals; D000906:Antibodies / Q000737:chemistry / Q000494:pharmacology*; D000970:Antineoplastic Agents / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology*; D016923:Cell Death / Q000187:drug effects; D045744:Cell Line, Tumor; D004220:Disulfides / Q000378:metabolism; D004354:Drug Screening Assays, Antitumor; D006031:Glycosylation / Q000187:drug effects; D006801:Humans; D013058:Mass Spectrometry; D051379:Mice; D008967:Molecular Biology / Q000379:methods*
D000906:Antibodies; D000970:Antineoplastic Agents; D004220:Disulfides