Affiliation:
1. Genentech Inc, South San Francisco, CA;
2. Haematological Malignancy Diagnostic Service, Leeds Teaching Hospitals, Leeds, United Kingdom; and
3. Department of Haematology, St James's Institute of Oncology, Leeds, United Kingdom
Abstract
Abstract
Here we describe the generation of an antibody–drug conjugate (ADC) consisting of a humanized anti-CD79b antibody that is conjugated to monomethylauristatin E (MMAE) through engineered cysteines (THIOMABs) by a protease cleavable linker. By using flow cytometry, we detected the surface expression of CD79b in almost all non-Hodgkin lymphoma (NHL) and chronic lymphocytic leukemia patients, suggesting that anti–CD79b-vcMMAE could be widely used in these malignancies. By using NHL cell lines to simulate a patient population we discovered that a minimal cell-surface expression level of CD79b was required for in vitro activity. Within the subpopulation of cell lines above this minimal threshold, we found that sensitivity to free MMAE, mutation of cancer genes, and cell doubling time were poorly correlated with in vitro activity; however, the expression level of BCL-XL was correlated with reduced sensitivity to anti–CD79b-vcMMAE. This observation was supported by in vivo data showing that a Bcl-2 family inhibitor, ABT-263, strikingly enhanced the activity of anti–CD79b-vcMMAE. Furthermore, anti–CD79b-vcMMAE was significantly more effective than a standard-of-care regimen, R-CHOP (ie, rituximab with a single intravenous injection of 30 mg/kg cyclophosphamide, 2.475 mg/kg doxorubicin, 0.375 mg/kg vincristine, and oral dosing of 0.15 mg/kg prednisone once a day for 5 days), in 3 xenograft models of NHL. Together, these data suggest that anti–CD79b-vcMMAE could be broadly efficacious for the treatment of NHL.
Publisher
American Society of Hematology
Subject
Cell Biology,Hematology,Immunology,Biochemistry
Reference27 articles.
1. Non-Hodgkin lymphoma: an update.;Hennessy;Lancet Oncol,2004
2. SEER Cancer Statistics Review, 1975-2005;Ries
3. Antibody-drug conjugates for cancer therapy.;Carter;Cancer J,2008
4. Arming antibodies for cancer therapy [review].;Polakis;Curr Opin Pharmacol,2005
5. Approval summary: gemtuzumab ozogamicin in relapsed acute myeloid leukemia.;Bross;Clin Cancer Res,2001
Cited by
197 articles.
订阅此论文施引文献
订阅此论文施引文献,注册后可以免费订阅5篇论文的施引文献,订阅后可以查看论文全部施引文献