An Anti-CD33 Antibody-Calicheamicin Conjugate for Treatment of Acute Myeloid Leukemia. Choice of Linker
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- 作者：Philip R. Hamann ; Lois M. Hinman ; Carl F. Beyer ; Delores Lindh ; Janis Upeslacis ; David A. Flowers ; and Irwin Bernstein
- 刊名：Bioconjugate Chemistry
- 出版年：2002
- 出版时间：January 2002
- 年：2002
- 卷：13
- 期：1
- 页码：40 - 46
- 全文大小：86K
- 年卷期：v.13,no.1(January 2002)
- ISSN：1520-4812
文摘
The anti-CD33 antibody, P67.6, has been chosen to target the potently cytotoxic calicheamicinantitumor antibiotics to acute myeloid leukemia (AML) due to the presence of CD33 on >80% of patientsamples and its lack of expression outside the myeloid cell lineages, especially its lack of expressionon pluripotent stem cells. Previous calicheamicin conjugates relied on the attachment of a hydrazidederivative to the oxidized carbohydrates that occur naturally on antibodies. This results in a"carbohydrate conjugate" capable of releasing active drug by hydrolysis of a hydrazone bond in thelysozomes where the pH is low. Conjugates have now been made that are formed by reacting acalicheamicin derivative containing an activated ester with the lysines of antibodies. This results inan "amide conjugate" that is stable to hydrolysis, leaving the disulfide that is present in allcalicheamicin conjugates as the likely site of drug release from the conjugate. In this article, thesetwo classes of calicheamicin-antibody conjugates are compared for potential use in AML with theanti-CD33 antibody P67.6. Conjugates of P67.6 are shown to require the site of hydrolytic releaseafforded by the carbohydrate conjugates in order to retain good potency and selectivity in vitro, invivo, and ex vivo. The P67.6 carbohydrate conjugate of calicheamicin is selectively cytotoxic at <0.006ng/mL of calicheamicin equivalents (cal equiv) toward HL-60 promyelocytic leukemia cells in tissueculture. Long-term, tumor-free survivors are seen in xenograft models when mice bearing HL-60subcutaneous tumors are treated with the P67.6 carbohydrate conjugate at a dose of 300 
g/kg calequiv given three times. This conjugate also selectively inhibits the formation of colonies from AMLmarrow samples at 2 ng/mL cal equiv. The P67.6 carbohydrate conjugate of calicheamicin thereforeappears to have promise as an antibody-targeted chemotherapeutic agent for CD33-positive diseasessuch as AML.
g/kg calequiv given three times. This conjugate also selectively inhibits the formation of colonies from AMLmarrow samples at 2 ng/mL cal equiv. The P67.6 carbohydrate conjugate of calicheamicin thereforeappears to have promise as an antibody-targeted chemotherapeutic agent for CD33-positive diseasessuch as AML.