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Gemtuzumab Ozogamicin, A Potent and Selective Anti-CD33 Antibody−Calicheamicin Conjugate for Treatment of Acute Myeloid Leukemia

Hamann, Philip R., Hinman, Lois M., Hollander, Irwin, Beyer, Carl F., Lindh, Delores, Holcomb, Ryan, Hallett, William, Tsou, Hwei-Ru, Upeslacis, Janis, Shochat, Dan, Mountain, Andrew, Flowers, David A., Bernstein, Irwin·2002·Bioconjugate Chemistry
DOI 10.1021/bc010021y
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Abstract

CD33 is expressed by acute myeloid leukemia (AML) cells in >80% of patients but not by normal hematopoietic 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 oxidized carbohydrates of the anti-CD33 murine antibody P67.6 had been chosen for use in AML prior to humanization of this antibody. However, the CDR-grafted humanized P67.6 could not be used to make the 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 but incorporates 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 carbohydrate conjugate it replaced. It was selectively cytotoxic to HL-60 leukemia cells in tissue culture with an IC(50) in the low to sub-pg cal/mL range (cal = calicheamicin equivalents). Doses of gem-ozo as low as 50 microg 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 concentration of 2 to 10 ng cal/mL selectively inhibited leukemia colony formation by marrow cells from a significant proportion of AML patients. Gem-ozo has also shown significant activity against AML in Phase II trials and is the first antibody-targeted chemotherapeutic agent approved by the FDA.

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Authors
Hamann, P. R., Hinman, L. M., Hollander, I., Beyer, C. F., Lindh, D., Holcomb, R., Hallett, W., Tsou, H.-R., Upeslacis, J., Shochat, D., Mountain, A., Flowers, D. A., & Bernstein, I.
Venue
Bioconjugate Chemistry
Publisher
American Chemical Society (ACS)
Published
2001-12-19
Volume
13
Issue
1
Pages
47-58
ISSN
  • 1043-1802 (ISSN-L)
  • 1520-4812
DOI
10.1021/bc010021y
OpenAlex
W2077248326
Cited by
594
References
0
FWCI
5.82
Type
journal article
Language
en
Open access
closed

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