Tumour-targeted chemotherapy with immunoconjugates of calicheamicin.
Antibody-targeted chemotherapy is a therapeutic strategy in cancer therapy that involves a monoclonal antibody specific for a tumour-associated antigen, covalently linked via a suitable linker to a potent cytotoxic agent. Tumour-targeted delivery of a cytotoxic agent in the form of an immunoconjugate is expected to improve its antitumour activity and safety. Calicheamicin is a cytotoxic natural product isolated from Micromonospora echinospora that is at least 1000-fold more potent than conventional cytotoxic chemotherapeutics. Calicheamicin binds DNA in the minor groove and causes double-strand DNA breaks, leading to cell death. Immunoconjugates of calicheamicin targeted against tumour-associated antigens exhibit tumour-specific cytotoxic effects and cause regression of established human tumour xenografts in nude mice. Gemtuzumab ozogamicin is the first clinically validated cytotoxic immunoconjugate in which a humanised anti-CD33 antibody is linked to a derivative of calicheamicin. Gemtuzumab ozogamicin is indicated for the treatment of elderly patients with relapsed acute myeloid leukaemia. A similar conjugate, inotuzumab ozogamicin, is being evaluated at present in Phase I clinical trials in patients with non-Hodgkin's lymphoma. A number of tumour-targeted immunoconjugates of calicheamicin are being explored preclinically at present for their therapeutic applications.
Damle
Nitin K
NK
Oncology Discovery Research, Wyeth Pharmaceuticals, 200/4604, 401 North Middletown Road, Pearl River, NY 10965, USA. damlen@wyeth.com
D000368:Aged; D000617:Aminoglycosides / Q000008:administration & dosage / Q000009:adverse effects / Q000627:therapeutic use*; D000818:Animals; D000911:Antibodies, Monoclonal / Q000008:administration & dosage / Q000009:adverse effects / Q000627:therapeutic use; D061067:Antibodies, Monoclonal, Humanized; D015703:Antigens, CD / Q000276:immunology; D015214:Antigens, Differentiation, Myelomonocytic / Q000276:immunology; D000951:Antigens, Neoplasm / Q000276:immunology; D017321:Clinical Trials, Phase I as Topic; D017322:Clinical Trials, Phase II as Topic; D004249:DNA Damage; D016503:Drug Delivery Systems; D053281:Enediynes; D005260:Female; D000079982:Gemtuzumab; D006402:Hematologic Diseases / Q000139:chemically induced; D019337:Hematologic Neoplasms / Q000188:drug therapy; D006504:Hepatic Veno-Occlusive Disease / Q000139:chemically induced; D006801:Humans; D018796:Immunoconjugates / Q000627:therapeutic use*; D000080045:Inotuzumab Ozogamicin; D051379:Mice; D008819:Mice, Nude; D008875:Middle Aged; D009369:Neoplasms / Q000188:drug therapy*; D010051:Ovarian Neoplasms / Q000188:drug therapy; D063268:Sialic Acid Binding Ig-like Lectin 3; D023041:Xenograft Model Antitumor Assays
D000617:Aminoglycosides; D000911:Antibodies, Monoclonal; D061067:Antibodies, Monoclonal, Humanized; D015703:Antigens, CD; D015214:Antigens, Differentiation, Myelomonocytic; D000951:Antigens, Neoplasm; C571163:CD33 protein, human; C571165:Cd33 protein, mouse; D053281:Enediynes; D018796:Immunoconjugates; D063268:Sialic Acid Binding Ig-like Lectin 3; C421256:hCTMO1-calicheamicin; C055955:calicheamicin gamma(1)I; D000079982:Gemtuzumab; D000080045:Inotuzumab Ozogamicin