Monoclonal Antibody Cytotoxic Conjugates

gemtuzumab ozogamicin Gemtuzumab ozogamicin (mylotarg) comprises a monoclonal antibody against CD33 covalently linked to a semisynthetic derivative of calicheam-icin, a potent enediyne antitumor antibiotic. The CD33 antigen is found on most hematopoietic cells, on >80% of AML, and in most myelodysplasias. Following binding to CD33, gemtuzumab ozogamicin undergoes endocytosis with cleavage of calicheamicin within the lysosome, which ultimately causes double-strand DNA breaks and cell death. Gemtuzumab ozogamicin is FDA-approved for the treatment of CD33-positive AML in first relapse in patients >60 years old who are not candidates for conventional cytotoxic therapy. Studies exploring new roles for gemtuzumab ozogamicin are being conducted, including treatment of refractory and previously untreated AML.

Pharmacokinetics of gemtuzumab ozogamicin at the standard 9 mg/m2 dose showed half-lives of total and unconjugated calicheamicin of 41 and 143 hours, respectively. Following a second dose, the t/^ increased to 64 hours and the AUC was twice that of the initial dose. Serious toxicities may occur with gemtuzumab ozogamicin. Like other monoclonal antibodies, infusion-related toxicities occur with the first infusion but are ameliorated by glucocorticoids. The primary toxicities are bone marrow suppression and hepatic toxicity. Hepatic toxicity can be serious and may lead to fatal VOD. In the phase 2 study, significant hyperbilirubinemia was observed in 23% of patients; this may represent subclinical VOD in some cases.

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