Pharmacokinetics and immune response

Serum concentrations of the hP67.6 and calicheamicin component of gem-tuzumab ozogamicin and peripheral blast saturation were measured in the phase I and II studies (23). The half-life of hP67.6 was approx 67 h, and the peak concentration was proportional to the dose. The free calicheamicin area

Fig. 6. Illustration showing the molecular structure of gemtuzumab ozogamicin. The hP67.6 is the humanized anti-CD33 antibody shown as a circle, which is attached through an e amino group of lysine to an Ac-But acid labile linker and, finally, to calicheamicin 1y1.

Fig. 6. Illustration showing the molecular structure of gemtuzumab ozogamicin. The hP67.6 is the humanized anti-CD33 antibody shown as a circle, which is attached through an e amino group of lysine to an Ac-But acid labile linker and, finally, to calicheamicin 1y1.

Fig. 7. Cell intoxication by gemtuzumab ozogamicin: (a) binding to cell surface CD33; (b) internalization to endosomes; (c) cleavage of acid labile bond and release of calicheamicin; (d) diffusion through endosome or lysosome membrane bilayer to cytosol; (e) reduction of disulfide followed by diradical formation; (f) insertion into DNA and double-strand DNA cleavage; and (g) programmed cell death.

Fig. 7. Cell intoxication by gemtuzumab ozogamicin: (a) binding to cell surface CD33; (b) internalization to endosomes; (c) cleavage of acid labile bond and release of calicheamicin; (d) diffusion through endosome or lysosome membrane bilayer to cytosol; (e) reduction of disulfide followed by diradical formation; (f) insertion into DNA and double-strand DNA cleavage; and (g) programmed cell death.

under the concentration curve was 0.3% of the hP67.6 area under the concentration curve. Saturation of circulating blasts was observed at 4 mg/m2 or greater.

Antibodies to gemtuzumab ozogamicin were measured in all of the clinical trials. In the phase I study, one patient developed antibody to the calicheam-icin-linker complex after the third dose and a second patient developed antibodies to the calicheamicin-linker during the second dose of a second course of gemtuzumab ozogamicin. In the phase II studies, no humoral immune response to gemtuzumab ozogamicin occurred in the 188 evaluable patients.

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