Gemtuzumab Ozogamicin, A Potent and Selective Anti-CD33 Antibody-Calicheamicin Conjugate for Treatment of Acute Myeloid Leukemia
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- 作者：Philip R. Hamann ; Lois M. Hinman ; Irwin Hollander ; Carl F. Beyer ; Delores Lindh ; Ryan Holcomb ; William Hallett ; Hwei-Ru Tsou ; Janis Upeslacis ; Dan Shochat ; Andrew Mountain ; David A. Flowers ; and Irwin
- 刊名：Bioconjugate Chemistry
- 出版年：2002
- 出版时间：January 2002
- 年：2002
- 卷：13
- 期：1
- 页码：47 - 58
- 全文大小：147K
- 年卷期：v.13,no.1(January 2002)
- ISSN：1520-4812
文摘
CD33 is expressed by acute myeloid leukemia (AML) cells in >80% of patients but not by normalhematopoietic stem cells, suggesting that elimination of CD33+ cells may be therapeutically beneficial.A conjugate of a calicheamicin hydrazide derivative attached via hydrazone formation to the oxidizedcarbohydrates of the anti-CD33 murine antibody P67.6 had been chosen for use in AML prior tohumanization of this antibody. However, the CDR-grafted humanized P67.6 could not be used to makethe carbohydrate conjugate because of the unexpected sensitivity of this antibody to periodate oxidation.Exploration of a series of bifunctional linkers resulted in a new class of calicheamicin conjugates,termed the hybrid conjugates, that allows for the attachment of the calicheamicin to lysines butincorporates the site of hydrolytic release, a hydrazone, previously shown to be required for activity.The optimized conjugate chosen for clinical trials, gemtuzumab ozogamicin ("gem-ozo", Mylotarg,formerly designated CMA-676), was significantly more potent and selective than the carbohydrateconjugate it replaced. It was selectively cytotoxic to HL-60 leukemia cells in tissue culture with anIC50 in the low to sub-pg cal/mL range (cal = calicheamicin equivalents). Doses of gem-ozo as low as50 
g cal/kg given three times to mice bearing HL-60 xenografts routinely resulted in long-term, tumor-free survivors, while a nonbinding control conjugate was relatively inactive. Gem-ozo at a concentrationof 2 to 10 ng cal/mL selectively inhibited leukemia colony formation by marrow cells from a significantproportion of AML patients. Gem-ozo has also shown significant activity against AML in Phase IItrials and is the first antibody-targeted chemotherapeutic agent approved by the FDA.
g cal/kg given three times to mice bearing HL-60 xenografts routinely resulted in long-term, tumor-free survivors, while a nonbinding control conjugate was relatively inactive. Gem-ozo at a concentrationof 2 to 10 ng cal/mL selectively inhibited leukemia colony formation by marrow cells from a significantproportion of AML patients. Gem-ozo has also shown significant activity against AML in Phase IItrials and is the first antibody-targeted chemotherapeutic agent approved by the FDA.