Chapter 5: The Genesis of the Antibody Conjugate Gemtuzumab Ozogamicin (Mylotarg®) for Acute Myeloid Leukemia

Gemtuzumab ozogamicin is an antibody conjugate of calicheamicin that targets the CD33 antigen on differentiating myeloid cells and which is over-expressed on acute myeloid leukemia cells in most patients. It carries a DNA-active calicheamicin derivative selected during preclinical work with various antibodies. The calicheamicin derivative is attached to the hP67.6 antibody via the bifunctional AcBut linker, which allows for hydrolytic release of the calicheamicin in the acidic lysosomes. This conjugate, hP67.6-NAc-gamma calicheamicin DMH AcBut, is potently cytotoxic to most CD33-positive cells in tissue culture with high selectivity versus CD33-negative cells. It is curative of the CD33-expressing HL-60 xenografts and shows selective cytotoxicity in a significant proportion of AML bone marrow samples in a colony-forming assay.

Gemtuzumab ozogamicin has shown significant activity in various clinical trials. In pivotal Phase 2 trials, the remission rate was 26% and the medium recurrence-free survival in a heavily pre-treated patient population was 5.5 months. It was approved by the FDA in May 2000 for use in patients with CD33-positive AML in first relapse who are ≥60 years of age and are not candidates for cytotoxic chemotherapy. In a key on-going study combining it with daunorubicin and cytarabine for first indication, a complete response (CR) rate of 84% with gemtuzumab ozogamicin vs. 55% without has been seen so far with a median duration of CR >6 months. Such studies promise to expand the role of gemtuzumab ozogamicin in the treatment of AML and to give patients more options for the treatment of this commonly fatal disease.