Design, Synthesis, and Biological Evaluation of Antibody-Drug Conjugates Comprised of Potent Camptothecin Analogues

被引：76

作者：

Burke, Patrick J. ^{[1
]}

Senter, Peter D. ^{[1
]}

Meyer, David W. ^{[1
]}

Miyamoto, Jamie B. ^{[1
]}

Anderson, Martha ^{[1
]}

Toki, Brian E. ^{[1
]}

Manikumar, Govindarajan ^{[2
]}

Wani, Mansukh C. ^{[2
]}

Kroll, David J. ^{[3
]}

Jeffrey, Scott C. ^{[1
]}

机构：

[1] Seattle Genet Inc, Bothell, WA 98021 USA

[2] Res Triangle Inst, Nat Prod Lab, Res Triangle Pk, NC 27709 USA

[3] N Carolina Cent Univ, BRITE, Durham, NC 27707 USA

来源：

BIOCONJUGATE CHEMISTRY | 2009年 / 20卷 / 06期

关键词：

TOPOISOMERASE-I INHIBITORS; CANCER-THERAPY; BREAST-CANCER; CURRENT PERSPECTIVES; DOXORUBICIN; PRODRUGS; BR96-DOXORUBICIN; IMMUNOCONJUGATE; RELEASE; VITRO;

D O I：

10.1021/bc9001097

中图分类号：

Q5 [生物化学];

学科分类号：

071010 ; 081704 ;

摘要：

Antibody-drug conjugates (ADCs) were prepared with potent camptothecin analogues attached to monoclonal antibodies (mAbs) via dipeptide or glucuronide-based linkers. Aniline-containing camptothecin analogues were employed to provide a site of linker attachment via carbamate bonds that would be stable in circulation. The camptothecin analogues, 7-butyl-10-amino-camptothecin and 7-butyl-9-amino-10,11-methylenedioxy-camptothecin, are generally 10-1000 times more potent than camptothecin. Dipeptide and glucuronide drug linkers were employed containing self-immolative spacers that release drug following lysosomal degradation upon ADC internalization into antigen-positive cell lines. The camplothecin drug linkers were conjugated to three antibodies: chimeric BR96, chimeric AC10, and humanized IF6, which bind to the Lewis-Y antigen on carcinomas, CD30 on hematologic malignancies, and CD70 present on hematologic malignancies and renal cell carcinoma, respectively. ADCs bearing the potent camptothecin analogue, 7-butyl-9-anlino-10,11-methylenedioxy-camptothecin, were highly potent and immunologically specific on a panel of cancer cell lines in vitro, and efficacious at well-tolerated doses in a renal cell carcinoma xenograft model.

引用

页码：1242 / 1250

页数：9

共 37 条

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