Mylotarg

Gemtuzumab ozogamicin is a CD33-directed antibody-drug conjugate (ADC). Gemtuzumab is a humanised immunoglobulin class G subtype 4 (IgG4) antibody which specifically recognizes human CD33. The antibody portion (hP67.6) binds specifically to the CD33 antigen, a sialic acid dependent adhesion protein found on the surface of myeloid leukaemic blasts and immature normal cells of myelomonocytic lineage, but not on normal haematopoietic stem cells. The small molecule, N-acetyl gamma calicheamicin, is a cytotoxic semisynthetic natural product. N-acetyl gamma calicheamicin is covalently attached to the antibody via an AcBut (4- (4'-acetylphenoxy) butanoic acid) linker. Nonclinical data suggest that the anticancer activity of gemtuzumab ozogamicin is due to the binding of the ADC to CD33-expressing tumour cells, followed by internalization of the ADC CD33 complex, and the intracellular release of N-acetyl gamma calicheamicin dimethyl hydrazide via hydrolytic cleavage of the linker. Activation of N-acetyl gamma calicheamicin dimethyl hydrazide induces double-stranded DNA breaks, subsequently inducing cell cycle arrest and apoptotic cell death.