Pharmacokinetics of Gemtuzumab Ozogamicin, an Antibody‐Targeted Chemotherapy Agent for the Treatment of Patients with Acute Myeloid Leukemia in First Relapse

Dowell, James A.; Korth‐Bradley, Joan M.; Liu, Hanjiu; King, Shang‐Ying P.; Berger, Mark S.

doi:10.1177/00912700122012751

Cited by 126 publications

(83 citation statements)

References 15 publications

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“…Using the AML-193 cell line as a model, we studied GOinduced cell death using a range of GO concentrations, based on the average GO concentration of approximately 3 mg/ml measured in the serum of AML patients after GO infusion. 11,26 Using blocking CD33 antibodies tested at 100 and 1000 times, the concentration needed to achieve complete CD33 saturation, we demonstrated complete CD33-mediated specificity of GO only at the lowest GO concentration tested (1 mg/ml). In contrast, the lysis induced by higher GO concentrations appeared to be only partially CD33 specific (Figure 1).…”

Section: Discussionmentioning

confidence: 89%

“…The complete inhibition of lysis was induced at the lowest GO concentration of 1 mg/ml. However, only half of the lysis induced by 3 mg/ml GO, which equals the average serum concentration measured in the peripheral blood of patients treated with GO, 11,26 could be inhibited by CD33 blockade, with 49714 and 40712% inhibition after 24 and 40 h, respectively. At higher GO concentrations, CD33 blockade using 500 mg/ml hP67.6 antibodies resulted in only marginal inhibition of lysis of 24719 and 21713% at 5 mg/ml GO after 24 and 40 h, respectively, or no inhibition at 10 mg/ml GO.…”

Section: Cd33 Specificity Of Go-induced Cell Deathmentioning

confidence: 84%

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Internalization and cell cycle-dependent killing of leukemic cells by Gemtuzumab Ozogamicin: rationale for efficacy in CD33-negative malignancies with endocytic capacity

et al. 2003

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Multicenter phase II trials with Gemtuzumab Ozogamicin (GO/ Mylotarg s ), consisting of a CD33 antibody linked to the cytotoxic drug calicheamicin, have shown a 30% overall response rate in relapsed acute myeloid leukemia patients. However, no clear correlation was observed between CD33 expression on leukemic blasts and response to GO therapy. We analyzed the CD33 specificity of GO-induced cell death and the effect of GO on CD33-negative malignancies. We demonstrate that lysis induced by clinically relevant GO concentrations is partially CD33 mediated, and that efficient non-CD33-mediated GO uptake can occur via endocytosis. In agreement with these results, we observed GO-mediated death of human CD33-negative acute lymphoblastic leukemia cells both in vitro and in vivo in an NOD/SCID mouse model. Finally, sensitivity to GOinduced cell death was at least partially determined by the activation status of leukemic cells, with cells in activated phases of the cell cycle being most effective in both CD33-specific GO internalization, renewed expression of CD33 molecules, and non-CD33-mediated GO uptake via endocytosis. In conclusion, these data provide mechanistic insight into the efficacy of GO in CD33-positive as well as in CD33-negative malignancies with endocytic capacity, and provide a rationale for the use of GO in the treatment of malignancies with endocytic capacity.

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Section: Discussionmentioning

confidence: 89%

Section: Cd33 Specificity Of Go-induced Cell Deathmentioning

confidence: 84%

Internalization and cell cycle-dependent killing of leukemic cells by Gemtuzumab Ozogamicin: rationale for efficacy in CD33-negative malignancies with endocytic capacity

et al. 2003

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“…ϩ myeloid leukemia (13). Maytansine derivatives represent a new class of highly cytotoxic agents suitable for conjugation with mAbs.…”

Section: Introductionmentioning

confidence: 99%

In Vitroandin VivoActivity of the Maytansinoid Immunoconjugate huN901-N2′-Deacetyl-N2′-(3-Mercapto-1-Oxopropyl)-Maytansine against CD56+ Multiple Myeloma Cells

et al. 2004

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ABSTRACT؉ OPM2 human MM cell line in SCID mice. We observed inhibition of serum paraprotein secretion, inhibition of tumor growth, and increase in survival of mice treated with huN901-DM1. Our data therefore demonstrate that huN901-DM1 has significant in vitro and in vivo antimyeloma activity at doses that are well tolerated in a murine model. Taken together, these data provide the framework for clinical trials of this agent to improve patient outcome in MM.

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“…19 Moreover, similar experiments on primary AML blasts demonstrated that these cells are even more susceptible to apoptosis induction by VPA and GO cotreatment (Figure 1f, CI of 0.75).…”

Section: Resultsmentioning

confidence: 60%

The histone deacetylase inhibitor valproic acid potently augments gemtuzumab ozogamicin-induced apoptosis in acute myeloid leukemic cells

et al. 2006

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Gemtuzumab ozogamicin (GO) is a calicheamicin-conjugated antibody directed against CD33, an antigen highly expressed on acute myeloid leukemic (AML) cells. CD33-specific binding triggers internalization of GO and subsequent hydrolytic release of calicheamicin. Calicheamicin then translocates to the nucleus, intercalates in the DNA structure and subsequently induces double-strand DNA breaks. GO is part of clinical practice for AML, but is frequently associated with severe side effects. Therefore, combination of GO with other therapeutics is warranted to reduce toxicity, while maximizing therapeutic selectivity. We hypothesized that the histone deacetylase inhibitor valproic acid (VPA) sensitizes AML cells to GO. VPAinduced histone hyperacetylation opens the chromatin structure, whereby the DNA intercalation of calicheamicin should be augmented. We found that clinically relevant concentrations of VPA potently augmented the tumoricidal activity of GO towards AML cell lines and primary AML blasts. Moreover, VPA treatment indeed augmented the DNA intercalation of calicheamicin and enhanced DNA degradation. Importantly, synergy was restricted to CD33-positive AML cells and did not require caspase activation. In conclusion, the synergistic proapoptotic activity of cotreatment of AML cells with VPA and GO indicates the potential value of this strategy for AML.

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Pharmacokinetics of Gemtuzumab Ozogamicin, an Antibody‐Targeted Chemotherapy Agent for the Treatment of Patients with Acute Myeloid Leukemia in First Relapse

Cited by 126 publications

References 15 publications

Internalization and cell cycle-dependent killing of leukemic cells by Gemtuzumab Ozogamicin: rationale for efficacy in CD33-negative malignancies with endocytic capacity

Internalization and cell cycle-dependent killing of leukemic cells by Gemtuzumab Ozogamicin: rationale for efficacy in CD33-negative malignancies with endocytic capacity

In Vitroandin VivoActivity of the Maytansinoid Immunoconjugate huN901-N2′-Deacetyl-N2′-(3-Mercapto-1-Oxopropyl)-Maytansine against CD56+ Multiple Myeloma Cells

The histone deacetylase inhibitor valproic acid potently augments gemtuzumab ozogamicin-induced apoptosis in acute myeloid leukemic cells

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