Antibody-Drug Conjugates for the Treatment of Non-Hodgkin's Lymphoma: Target and Linker-Drug Selection

被引：200

作者：

Polson, Andrew G. ^{[1
]}

Calemine-Fenaux, Jill ^{[1
]}

Chan, Pamela ^{[1
]}

Chang, Wesley ^{[1
]}

Christensen, Erin ^{[1
]}

Clark, Suzanna ^{[1
]}

de Sauvage, Frederic J. ^{[1
]}

Eaton, Dan ^{[1
]}

Elkins, Kristi ^{[1
]}

Elliott, J. Michael ^{[1
]}

Frantz, Gretchen ^{[1
]}

Fuji, Reina N. ^{[1
]}

Gray, Alane ^{[1
]}

Harden, Kristin ^{[1
]}

Ingle, Gladys S. ^{[1
]}

Kljavin, Noelyn M. ^{[1
]}

Koeppen, Hartmut ^{[1
]}

Nelson, Christopher ^{[1
]}

Prabhu, Saileta ^{[1
]}

Raab, Helga ^{[1
]}

Ross, Sarajane ^{[1
]}

Stephan, Jean-Philippe ^{[1
]}

Scales, Suzie J. ^{[1
]}

Spencer, Susan D. ^{[1
]}

Vandlen, Richard ^{[1
]}

Wranik, Bernd ^{[1
]}

Yu, Shang-Fan ^{[1
]}

Zheng, Bing ^{[1
]}

Ebens, Allen ^{[1
]}

机构：

[1] Genentech Inc, San Francisco, CA 94080 USA

来源：

CANCER RESEARCH | 2009年 / 69卷 / 06期

关键词：

MONOCLONAL-ANTIBODIES; EXPRESSION; TECHNOLOGY; DELIVERY; PEPTIDE;

D O I：

10.1158/0008-5472.CAN-08-2250

中图分类号：

R73 [肿瘤学];

学科分类号：

100214 ;

摘要：

Antibody-drug conjugates (ADC), potent cytotoxic drugs covalently linked to antibodies via chemical linkers, provide a means to increase the effectiveness of chemotherapy by targeting the drug to neoplastic cells while reducing side effects. Here, we systematically examine the potential targets and linker-drug combinations that could provide an optimal ADC for the treatment for non-Hodgkin's lymphoma. We identified seven antigens (CD19, CD20, CD21, CD22, CD72, CD79b, and CD180) for potential treatment of non-Hodgkin's lymphoma with ADCs. ADCs with cleavable linkers mediated in vivo efficacy via all these targets; ADCs with uncleavable linkers were only effective when targeted to CD22 and CD79. In target-independent safety studies in rats, the uncleavable linker ADCs showed reduced toxicity, presumably due to I e reduced release of free drug or other toxic metabolites into the circulation. Thus, our data suggest that ADCs with cleavable linkers work on a broad range of targets, and for specific targets, ADCs with uncleavable linkers provide a promising opportunity to improve the therapeutic window for ADCs in humans. [Cancer Res 2009;69(6):2358-64]

引用

页码：2358 / 2364

页数：7

共 28 条

[1]

Barclay AN., 1997, LEUCOCYTE ANTIGEN FA

[2]

Bross PF, 2001, CLIN CANCER RES, V7, P1490

[3]

Cabezudo E, 1999, HAEMATOLOGICA, V84, P413

[4]

D'Arena G, 2000, AM J HEMATOL, V64, P275