Tumour-targeted chemotherapy with immunoconjugates of calicheamicin.

Abstract

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.

• Authors: Nitin K Damle
• Journal: Expert opinion on biological therapy (Expert Opin Biol Ther) Vol. 4 Issue 9 Pg. 1445-52 (Sep 2004) ISSN: 1744-7682 [Electronic] England
• PMID: 15335312 (Publication Type: Journal Article, Review)

Chemical References

• Aminoglycosides
• Antibodies, Monoclonal
• Antibodies, Monoclonal, Humanized
• Antigens, CD
• Antigens, Differentiation, Myelomonocytic
• Antigens, Neoplasm
• CD33 protein, human
• Cd33 protein, mouse
• Enediynes
• Immunoconjugates
• Sialic Acid Binding Ig-like Lectin 3
• hCTMO1-calicheamicin
• calicheamicin gamma(1)I
• Gemtuzumab
• Inotuzumab Ozogamicin

Topics

• Aged
• Aminoglycosides (administration & dosage, adverse effects, therapeutic use)
• Animals
• Antibodies, Monoclonal (administration & dosage, adverse effects, therapeutic use)
• Antibodies, Monoclonal, Humanized
• Antigens, CD (immunology)
• Antigens, Differentiation, Myelomonocytic (immunology)
• Antigens, Neoplasm (immunology)
• Clinical Trials, Phase I as Topic
• Clinical Trials, Phase II as Topic
• DNA Damage
• Drug Delivery Systems
• Enediynes
• Female
• Gemtuzumab
• Hematologic Diseases (chemically induced)
• Hematologic Neoplasms (drug therapy)
• Hepatic Veno-Occlusive Disease (chemically induced)
• Humans
• Immunoconjugates (therapeutic use)
• Inotuzumab Ozogamicin
• Mice
• Mice, Nude
• Middle Aged
• Neoplasms (drug therapy)
• Ovarian Neoplasms (drug therapy)
• Sialic Acid Binding Ig-like Lectin 3
• Xenograft Model Antitumor Assays