Anti-CD22-MCC-DM1: an antibody-drug conjugate with a stable linker for the treatment of non-Hodgkin's lymphoma

被引：74

作者：

Polson, A. G. ^{[1
]}

Williams, M. ^{[1
]}

Gray, A. M. ^{[1
]}

Fuji, R. N. ^{[1
]}

Poon, K. A. ^{[1
]}

McBride, J. ^{[1
]}

Raab, H. ^{[1
]}

Januario, T. ^{[1
]}

Go, M. ^{[1
]}

Lau, J. ^{[1
]}

Yu, S-F ^{[1
]}

Du, C. ^{[1
]}

Fuh, F. ^{[1
]}

Tan, C. ^{[1
]}

Wu, Y. ^{[1
]}

Liang, W-C ^{[1
]}

Prabhu, S. ^{[1
]}

Stephan, J-P ^{[1
]}

Hongo, J-A ^{[1
]}

Dere, R. C. ^{[1
]}

Deng, R. ^{[1
]}

Cullen, M. ^{[2
,3
]}

de Tute, R. ^{[2
,3
]}

Bennett, F. ^{[2
,3
]}

Rawstron, A. ^{[2
,3
]}

Jack, A. ^{[3
]}

Ebens, A. ^{[1
]}

机构：

[1] Genentech Inc, Res & Early Dev, San Francisco, CA 94080 USA

[2] Leeds Teaching Hosp, Haematol Malignancy Diagnost Serv, Leeds, W Yorkshire, England

[3] St Jamess Inst Oncol, Dept Haematol, Bexley Wing, Leeds, W Yorkshire, England

来源：

LEUKEMIA | 2010年 / 24卷 / 09期

关键词：

CD22; immuno-conjugates; non-Hodgkin's lymphoma; B-cell receptor; antibody drug conjugates; INOTUZUMAB OZOGAMICIN; ANTITUMOR EFFICACY; CANCER; CALICHEAMICIN; IMMUNOCONJUGATE; EXPRESSION; CMC-544; TARGET;

D O I：

10.1038/leu.2010.141

中图分类号：

R73 [肿瘤学];

学科分类号：

100214 ;

摘要：

Antibody-drug conjugates (ADCs) are potent cytotoxic drugs linked to antibodies through chemical linkers, and allow specific targeting of drugs to neoplastic cells. The expression of CD22 is limited to B-cells, and we show that CD22 is expressed on the vast majority of non-Hodgkin's lymphomas (NHLs). An ideal target for an ADC for the treatment of NHL would have limited expression outside the B-cell compartment and be highly effective against NHL. We generated an ADC consisting of a humanized anti-CD22 antibody conjugated to the anti-mitotic agent maytansine with a stable linker (anti-CD22-MCC-DM1). Anti-CD22-MCC-DM1 was broadly effective in in vitro killing assays on NHL B-cell lines. We did not find a strong correlation between in vitro potency and CD22 surface expression, internalization of ADC or sensitivity to free drug. We show that anti-CD22-MCC-DM1 was capable of inducing complete tumor regression in NHL xenograft mouse models. Further, anti-CD22-MCC-DM1 was well tolerated in cynomolgus monkeys and substantially decreased circulating B-cells as well as follicle size and germinal center formation in lymphoid organs. These results suggest that anti-CD22-MCC-DM1 has an efficacy, safety and pharmacodynamic profile that support its use as a treatment for NHL. Leukemia (2010) 24, 1566-1573; doi:10.1038/leu.2010.141; published online 1 July 2010

引用

页码：1566 / 1573

页数：8

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