Calicheamicin conjugates

A complete response in heavily pretreated relapsed or resistant AML patients was seen in 26% of 277 patients treated in a pivotal, open-label, single-arm Phase II trial. About half of the patients failed to recover normal platelet numbers, but were asymptomatic and transfusion free. Recurrence-free survival was 5.5 months. Gem Ozo 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 or older and are not candidates for cytotoxic chemotherapy. A significant advantage of Gem Ozo is the reduced toxicity versus traditional chemotherapy, which allows many patients to be treated on an out-patient basis, reducing hospitalization costs. 

In an initial Phase I study of Ino Ozo, an MTD of l.Smgm was seen. Common toxicities were thrombocytopenia, neutropenia, elevated liver enzymes, and the common infusion-related toxicities, with hematopoetic toxicities, especially thrombocytopenia, being the most common dose-limiting toxicity (DLT). Complete responses were observed starting at 0.8mgm . At the MTD in a heavily pretreated patient population, the objective response rates were 69% for follicular lymphoma and 33% for DLBCL as monotherapy.  

Subsequent studies have focused on combining Ino Ozo with rituximab. This combination has been supported by preclinical pharmacology studies, where an additive effect was seen between the two therapies with no apparent effect on the MTD of Ino Ozo. This was confirmed in cKnical studies, where Ino Ozo had the same MTD with or without rituximab with a similar profile of toxicities. The reported interim 6-month progression free survival rate was 100% for FL and 66% DLBCL for all patients in the MTD cohort. Ino Ozo is now in a Phase III clinical trial for foKcular NHL. 

In a Phase I clinical trail, half-lives of around 100 h were seen for various doses.Even though this is less than the native antibody, it is not unusual compared with other conjugates. However, when CMD-193 labeled with in was examined in a PK study, prolonged liver uptake was observed with little tumor uptake. The liver toxicity was also more pronounced than with previous calicheamicin conjugates. Although there is no direct data on the cause of these effects, it is possible that the choice of the IgGi isotype combined with the 

It should also be mentioned that there have been publications of conjugates of a synthetic calicheamicin analog, calicheamicin conjugated through 

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Gemtuzumab-oxogamici (anti CD33-calicheamicin conjugate) recombinant humanized IgG ... 

Hamann, P. R., Hinman, L. M., Hollander, I., et al. (2002) Gemtuzumab ozogamicin, a potent and selective anti-CD33 antibody-calicheamicin conjugate for treatment of acute myeloid leukemia. Bioconjugate Chemistry, 13, 47-58. 

Encouraging results with MAb-drug conjugates were seen in a phase I study with a conjugate of calicheamicin yli and a humanized anti-CD33 MAb in patients with refractory or relapsed AML [131]. Results support further evaluation in a setting of newly diagnosed or minimal-residual disease. 

A. General description Gemtuzumab ozogamicin is composed of a recombinant humanized IgG4, kappa antibody conjugated with a cytotoxic antitumor antibiotic, calicheamicin. The anti-CD33 antibody is produced by mammalian cell suspension... 

Recombinant humanized IgG4 kappa monoclonal antibody conjugated with calicheamicin chemotherapy agent, binds to CD33 on leukemic blasts and immature normal cells of... 

Other cardiovascular safety in dogs, in vitro blood compatibility, derivatives of gamma calicheamicin on murine bone marrow hematopoietic colony formation in vitro in vitro stability of hP67.6 conjugate in human, monkey, and rat plasma... 

Gemtuzumab ozogamicin (Mylotarg) consists of a humanized anti-CD33 monoclonal antibody conjugated to the cytotoxic enediyne antibiotic calicheamicin. It has been used to treat a subset of patients with acute myeloid leukemia in association with topotecan -I- cytarabine. Its most common adverse effects are myelosuppression, increased hepatic enzyme activity, infections, fever and chills, bleeding, nausea and vomiting, and dyspnea. 

Gemtuzumab ozogamicin is a humanized lgG4, kappa antibody conjugated with a cytotoxic antitumor or antibiotic, calicheamicin via a bifunctional linker. It has a MW of 151-153 kDa. 

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