calicheamicin-gamma(1)i and Hematologic-Diseases

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.

Topics: Aged; Aminoglycosides; Animals; Antibodies, Monoclonal; Antibodies, Monoclonal, Humanized; Antigens, CD; Antigens, Differentiation, Myelomonocytic; Antigens, Neoplasm; Clinical Trials, Phase I as Topic; Clinical Trials, Phase II as Topic; DNA Damage; Drug Delivery Systems; Enediynes; Female; Gemtuzumab; Hematologic Diseases; Hematologic Neoplasms; Hepatic Veno-Occlusive Disease; Humans; Immunoconjugates; Inotuzumab Ozogamicin; Mice; Mice, Nude; Middle Aged; Neoplasms; Ovarian Neoplasms; Sialic Acid Binding Ig-like Lectin 3; Xenograft Model Antitumor Assays