title: What Can We Learn about Antibody-Drug Conjugates from the T-DM1 Experience?
abstract: Antibody conjugates are a diverse class of therapeutics that consist of a cytotoxic agent linked covalently to an antibody or antibody fragment directed toward a specific cell surface target expressed by tumor cells. The notion that antibodies directed toward targets on the surface of malignant cells could be used for drug delivery is not new. The history of antibody conjugates has been marked by hurdles identified and overcome. Early conjugates used mouse antibodies, drugs that either were not sufficiently potent, were immunogenic (proteins), or were too toxic, and linkers that were not sufficiently stable in circulation. Four main avenues have been explored using antibodies to target cytotoxic agents to malignant cells: antibody-protein toxin (or antibody fragment-protein toxin fusion) conjugates, antibody-chelated radionuclide conjugates, antibody-small molecule conjugates, and antibody-enzyme conjugates administered along with small molecule prodrugs that require metabolism by the conjugated enzyme to release the activated species. Technology is continuing to evolve regarding the protein and small molecule components, and it is likely that single chemical entities soon will be the norm for antibody-drug conjugates. Only antibody-radionuclide conjugates and antibody-drug conjugates have reached the regulatory approval stage, and there are more than 40 antibody conjugates in clinical trials. The time may have come for this technology to become a major contributor to improving treatment for patients with cancer.
authors.affiliation: From the Laura and Isaac Perlmutter Cancer Center, NYU Langone Medical Center, New York, NY; Indiana University Melvin and Bren Simon Cancer Center, Indianapolis, IN; National Cancer Institute at the National Institutes of Health, Bethesda, MD.
authors.forename: Francisco J
authors.initials: FJ
authors.lastname: Esteva
authors.affiliation: From the Laura and Isaac Perlmutter Cancer Center, NYU Langone Medical Center, New York, NY; Indiana University Melvin and Bren Simon Cancer Center, Indianapolis, IN; National Cancer Institute at the National Institutes of Health, Bethesda, MD.
authors.forename: Kathy D
authors.initials: KD
authors.lastname: Miller
authors.affiliation: From the Laura and Isaac Perlmutter Cancer Center, NYU Langone Medical Center, New York, NY; Indiana University Melvin and Bren Simon Cancer Center, Indianapolis, IN; National Cancer Institute at the National Institutes of Health, Bethesda, MD.
authors.forename: Beverly A
authors.initials: BA
authors.lastname: Teicher
mesh_terms: D000080044:Ado-Trastuzumab Emtansine; D061067:Antibodies, Monoclonal, Humanized / Q000009:adverse effects / Q000627:therapeutic use*; D000970:Antineoplastic Agents / Q000009:adverse effects / Q000627:therapeutic use*; D006801:Humans; D018796:Immunoconjugates / Q000009:adverse effects / Q000627:therapeutic use*; D008453:Maytansine / Q000009:adverse effects / Q000031:analogs & derivatives* / Q000627:therapeutic use; D009369:Neoplasms / Q000188:drug therapy / Q000378:metabolism; D018719:Erb-b2 Receptor Tyrosine Kinases / Q000378:metabolism; D000068878:Trastuzumab
chemical_list: D000080044:Ado-Trastuzumab Emtansine; D061067:Antibodies, Monoclonal, Humanized; D000970:Antineoplastic Agents; D018796:Immunoconjugates; D008453:Maytansine; D018719:Erb-b2 Receptor Tyrosine Kinases; D000068878:Trastuzumab; C508053:ERBB2 protein, human