Gemtuzumab ozogamicin, a potent and selective anti-CD33 antibody-calicheamicin conjugate for treatment of acute myeloid leukemia.
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.
Hamann
Philip R
PR
Wyeth-Ayerst Research, 401 North Middletown Road, Pearl River, New York 10965, USA. hamannp@war.wyeth.com
Hinman
Lois M
LM
Hollander
Irwin
I
Beyer
Carl F
CF
Lindh
Delores
D
Holcomb
Ryan
R
Hallett
William
W
Tsou
Hwei-Ru
HR
Upeslacis
Janis
J
Shochat
Dan
D
Mountain
Andrew
A
Flowers
David A
DA
Bernstein
Irwin
I
D000208:Acute Disease; D000617:Aminoglycosides; D000818:Animals; D000900:Anti-Bacterial Agents / Q000627:therapeutic use*; D000911:Antibodies, Monoclonal / Q000627:therapeutic use*; D061067:Antibodies, Monoclonal, Humanized; D015703:Antigens, CD / Q000276:immunology*; D015214:Antigens, Differentiation, Myelomonocytic / Q000276:immunology*; D003432:Cross-Linking Reagents; D000079982:Gemtuzumab; D018922:HL-60 Cells; D006801:Humans; D000922:Immunotoxins / Q000627:therapeutic use*; D007202:Indicators and Reagents; D007951:Leukemia, Myeloid / Q000188:drug therapy*; D051379:Mice; D008819:Mice, Nude; D009368:Neoplasm Transplantation; D063268:Sialic Acid Binding Ig-like Lectin 3; D014407:Tumor Cells, Cultured
D000617:Aminoglycosides; D000900:Anti-Bacterial Agents; D000911:Antibodies, Monoclonal; D061067:Antibodies, Monoclonal, Humanized; D015703:Antigens, CD; D015214:Antigens, Differentiation, Myelomonocytic; C571163:CD33 protein, human; C571165:Cd33 protein, mouse; D003432:Cross-Linking Reagents; D000922:Immunotoxins; D007202:Indicators and Reagents; D063268:Sialic Acid Binding Ig-like Lectin 3; D000079982:Gemtuzumab